Preparation method of a cyclopropyl-substituted 2H-benzofuran derivative

Abstract

The present invention relates to the technical field of drug synthesis, and particularly relates to a preparation method of a cyclopropyl-substituted 2H-benzofuran derivative. In S100, intermediate I is prepared by using compound I, acid-binding agent I and compound II. This step effectively avoids the generation of impurity A and improves the purity and yield of intermediate I. In S200, intermediate II is prepared by using intermediate I, acid-binding agent II and compound III. This step effectively avoids the generation of impurity B and impurity C under high temperature and strong base conditions and improves the purity and yield of intermediate II. In S300, the cyclopropyl-substituted 2H-benzofuran derivative is prepared by using intermediate II. The results show that by using the preparation method provided by the present invention, the purity and yield of the target compound can be significantly improved, which is beneficial to the quality control of drug raw materials and can reduce its production cost.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a preparation method of a cyclopropyl-substituted 2H-benzofuran derivative. Background Art

[0002] A cyclopropyl-substituted 2H-benzofuran derivative with clinical potential for the treatment of pancreatitis has the following structural formula:

[0003] ;

[0004] The following preparation route is disclosed in the patent document WO2022179577A1:

[0005] ;

[0006] In this synthesis route, since the compound has an acyl chloride structure in its structural formula and its activity is relatively high, when preparing the intermediate , some disubstituted impurity A will be generated. The generation of impurity A will lead to a decrease in the purity and yield of the intermediate , and it is difficult to purify; when using the intermediate to prepare another intermediate , due to the relatively low activity of the amide in the structural formula of the intermediate , when reacting with the compound , it needs to react completely under strong bases (such as cesium carbonate, potassium carbonate, etc.) and high temperature conditions. The strong base and high temperature conditions will cause a lot of side reactants to be generated, mainly impurity B and impurity C , resulting in a decrease in the yield and purity of the intermediate . The generation mechanisms of impurity B and impurity C are as follows:

[0007] ;

[0008] Too many impurities generated during the preparation of the intermediate will reduce the purity and yield of the target compound 2H-benzofuran derivative.

[0009] Therefore, there is an urgent need for a preparation method with mild preparation conditions, simple operation, few impurities generated, and high purity of the intermediate and the target compound. Summary of the Invention

[0010] The present invention aims to solve at least one of the technical problems existing in the related art. For this reason, the purpose of the present invention is to provide a preparation method of a cyclopropyl-substituted 2H-benzofuran derivative.

[0011] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0012] A preparation method of a cyclopropyl-substituted 2H-benzofuran derivative, the structural formula of the cyclopropyl-substituted 2H-benzofuran derivative is as follows:

[0013] ;

[0014] Comprising the following steps:

[0015] S100. Using compound I , acid-binding agent I and compound II , to prepare intermediate I ;

[0016] Wherein, the acid-binding agent I is selected from organic bases;

[0017] S200. Using the intermediate I, acid-binding agent II and compound III , to prepare intermediate II ;

[0018] Wherein, the acid-binding agent II is selected from organic bases;

[0019] S300. Using the intermediate II to prepare the cyclopropyl-substituted 2H-benzofuran derivative.

[0020] Further, the process of step S100 is as follows:

[0021] At a temperature of 0-30°C, reaction solvent I is added to the reaction system. Under stirring conditions, compound I, acid-binding agent I and compound II are successively added. At a temperature of 25-35°C, after reacting for 6±0.5 h, water is added to the reaction system. After stirring evenly, it is left to stand, the aqueous phase is removed, and the organic phase is obtained. After drying and concentrating under reduced pressure, methyl tert-butyl ether is added, and after stirring and crystallizing for 1±0.5 h, it is filtered and dried to obtain intermediate I;

[0022] The process of step S200 is as follows: At a temperature of 0-30°C, reaction solvent II, the intermediate I and acid-binding agent II are added to the reaction system. Under stirring conditions, after the temperature is lowered to 0-10°C, compound III is added dropwise. After reacting for 3±0.5 h, water is added to the reaction system. After stirring evenly, it is left to stand, the aqueous phase is removed, and the organic phase is obtained. After concentrating it under reduced pressure, n-heptane and ethyl acetate are added, and after stirring and crystallizing for 2±0.5 h, it is filtered and dried to obtain intermediate II;

[0023] 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 with a pH of 3 are added to the reaction system. Then, the temperature is raised to 45°C. After reacting for 24 ± 1 h, the temperature is lowered to 0 - 30°C. After extraction and concentration, acetone is added to the reaction system. After stirring and dissolving, a tri(hydroxymethyl)aminomethane solution is added, and then the temperature is raised to 45 ± 0.5°C. After crystallization for 16 ± 1 h, the temperature is lowered to 23 ± 0.5°C, and after heat preservation and stirring for 2 ± 0.5 h, filtration is carried out to obtain a filter cake, which is dried to obtain a cyclopropyl-substituted 2H-benzofuran derivative.

[0024] Further, 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.

[0025] Further, the molar ratio of the acid-binding agent I to the amount of compound I added in step S100 is 1:1 - 4:1.

[0026] Further, 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.

[0027] Further, both the reaction solvent I and the reaction solvent II are selected from dichloromethane.

[0028] Further, the mass ratio of the amount of the reaction solvent I added in step S100 to the amount of compound I added is 3:1 - 15:1.

[0029] Further, the molar ratio of the acid-binding agent II to the amount of intermediate I added in step S200 is 1:1 - 4:1.

[0030] Further, the mass ratio of the amount of the reaction solvent II added in step S200 to the amount of intermediate I added is 3:1 - 15:1.

[0031] Further, the mass ratio of n-heptane to ethyl acetate added in step S200 is 4:1.

[0032] One or more of the above technical solutions in the embodiments of the present invention have at least one of the following technical effects:

[0033] A preparation method of a cyclopropyl-substituted 2H-benzofuran derivative provided by the present invention, step S100, uses an acid-binding agent I, a compound I and a compound II to generate an intermediate I, and this step effectively avoids the generation of impurity A and improves the purity and yield of the intermediate I; step S200, uses an acid-binding agent II, the intermediate I and a compound III to generate an intermediate II, and this step effectively avoids the generation of impurity B and impurity C under high temperature and strong base conditions and improves the purity and yield of the intermediate II; step S300, uses the intermediate II to prepare a cyclopropyl-substituted 2H-benzofuran derivative. The results show that using the preparation method provided by the present invention can significantly improve the purity (≥99.5%) and yield of the target compound, is beneficial to the quality control of drug raw materials, and can reduce its production cost.

[0034] Additional aspects and advantages of the present invention will be given in part in the following description, will become apparent in part from the following description, or will be understood through the practice of the present invention. Brief Description of the Drawings

[0035] Figure 1 It is the HPLC chromatogram of the intermediate I provided in Example 1 of the present invention.

[0036] Figure 2 It is the HNMR spectrum of the intermediate I provided in Example 1 of the present invention.

[0037] Figure 3 It is the HPLC chromatogram of the intermediate II provided in Example 1 of the present invention.

[0038] Figure 4 It is the HPLC chromatogram of the cyclopropyl-substituted 2H-benzofuran derivative provided in Example 1 of the present invention.

[0039] Figure 5 It is the HNMR spectrum of the cyclopropyl-substituted 2H-benzofuran derivative provided in Example 1 of the present invention.

[0040] Figure 6 It is the HPLC chromatogram of the intermediate I0 provided in Comparative Example 1 of the present invention.

[0041] Figure 7 It is the HPLC chromatogram of the intermediate II provided in Comparative Example 1 of the present invention.

[0042] 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 of the Embodiments

[0043] To make the objectives, technical solutions, and advantages of the present invention clearer, the following will clearly and completely describe the technical solutions in the present invention in combination with specific embodiments. Obviously, the described embodiments are some but not all of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in the present invention without any creative work fall 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.

[0044] A preparation method of a cyclopropyl-substituted 2H-benzofuran derivative, and its synthetic route is as follows:

[0045] 。

[0046] In the following examples and comparative examples, unless otherwise specified, the experimental methods used are all conventional methods. The materials, reagents, etc. used are carried out according to the techniques or conditions described in the literature in the field or according to the product instructions. Unless otherwise specified, they can all be obtained from commercial channels.

[0047] Example 1

[0048] I. Preparation of Intermediate I, the process is as follows:

[0049] At room temperature, add reaction solvent I dichloromethane (8.0 kg) to a 20 L reaction kettle, start stirring, and then sequentially add Compound I (1.0 kg), acid-binding agent I triethylamine (0.53 kg), and Compound II (0.95 kg). After the addition is complete, control the temperature in the reaction kettle at 25 °C. After reacting for 6 h, add purified water (5 kg) to the reaction kettle. After stirring for 20 min, remove the aqueous phase. The organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, then add methyl tert-butyl ether (8.5 kg), and stir and crystallize at room temperature for 1 h. Then filter and dry to obtain Intermediate I (1.65 kg); the detection result by high-performance liquid chromatography (HPLC) is as Figure 1 shown, and its nuclear magnetic resonance hydrogen spectrum (HNMR) is as Figure 2 shown;

[0050] Among them, the detected purity of Intermediate I is 99.6%, and the yield is 92.8%;

[0051] 1HNMR(CDCl3): δ(ppm) 8.40 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 8.06 - 8.07 (m, 1H), 7.08 (s, 1H), 6.87 - 6.88 (m, 1H), 5.80 (d, J = 8.0 Hz, 2H), 1.71 - 1.75 (m, 1H), 1.02 (s, 18H), 0.81 - 0.84 (m, 2H), 0.70 - 0.71 (m, 2H).

[0052] Among them, the reaction solvent I is not limited to dichloromethane, and can also be selected from at least one of chloroform, tetrahydrofuran, and N,N-dimethylformamide.

[0053] The acid-binding agent I is not limited to triethylamine, and can also be selected from at least one of N,N-diisopropylethylamine and pyridine.

[0054] II. Preparation of intermediate II, the process is as follows:

[0055] At room temperature, add dichloromethane (13.04 kg) as the reaction solvent II, the above-obtained intermediate I (1.63 kg), and triethylamine (0.49 kg) as the acid-binding agent II into a 20 L reaction kettle in sequence, start stirring, lower the temperature in the reaction kettle to 10 °C, and then dropwise add compound III (0.59 kg). After the addition is completed, control the temperature in the reaction kettle to 10 °C. After reacting for 3 h, add purified water (4 kg) to the reaction kettle, stir for 20 h, then remove the aqueous phase. The organic phase is dried with anhydrous sodium sulfate, concentrated under reduced pressure, and then add n-heptane (8.80 kg) and ethyl acetate (2.20 kg) to the system. Stir at room temperature, crystallize for 2 h, and then filter and dry to obtain intermediate II (1.86 kg). The HPLC detection results are as Figure 3 shown, the purity of intermediate II is 99.2%, and the yield is 89.4%;

[0056] Among them, the reaction solvent II is not limited to dichloromethane, and can also be selected from at least one of chloroform, tetrahydrofuran, and N,N-dimethylformamide. The reaction solvent II can be the same as or different from the reaction solvent I;

[0057] The acid-binding agent II is not limited to triethylamine, and can also be selected from at least one of N,N-diisopropylethylamine and pyridine. The acid-binding agent II can be the same as or different from the acid-binding agent I.

[0058] III. Preparation of cyclopropyl-substituted 2H-benzofuran derivatives, the process is as follows:

[0059] Under stirring, acetonitrile (15.80 kg) and the aforementioned obtained intermediate II (1.83 kg) were added to a 100 L reactor. Subsequently, a disodium hydrogen phosphate and citric acid buffer solution (6.65 kg) with a pH of 3 was added as a hydrolysis solution. After the addition was complete, the reaction solution was heated to 45 °C. After reacting for 24 h, the solution in the reactor was cooled to room temperature. Then, ethyl acetate (40.30 kg) and purified water (9.15 kg) were added to the reactor, and the mixture was stirred for extraction. The upper organic phase was retained. Then, an aqueous sodium bicarbonate solution with a concentration of 0.6 M (5.36 kg) was added to the organic phase, and after stirring, liquid separation was performed to retain the lower aqueous phase. Potassium bisulfate (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 again. After stirring and extracting again, the aqueous phase was discarded, and the upper organic phase was retained. After concentration under reduced pressure, acetone (18.30 kg) was added to the system. After stirring and dissolving, a tri(hydroxymethyl)aminomethane solution (0.67 kg) and purified water (1.83 kg) were added. After the addition was complete, the system was heated to 45 °C. After reacting for 16 h, the reaction solution was cooled to 23 °C and stirred at this temperature for 2 h. Then, the solvent was removed by filtration to obtain a filter cake, which was dried to obtain a cyclopropyl-substituted 2H-benzofuran derivative (1.56 kg). , and its HPLC detection results are as Figure 4 shown, and the HNMR is as Figure 5 shown;

[0060] The detected purity of the cyclopropyl-substituted 2H-benzofuran derivative is 99.5%, and the yield is 70.9%;

[0061] 1 HNMR (DMSO -d6 ) δ (ppm): 8.87 (s, 1H), 8.59 (s, 1H), 7.70 (s, 2H), 7.40 - 7.56 (m, 1H), 7.09 (s, 2H), 6.64 (s, 1H), 5.56 (d, J = 4.0 Hz, 2H), 5.3 (brs, 12H), 3.31 (s, 12H), 2.13 - 2.20 (m, 1H), 1.03 - 1.07 (m, 2H), 0.92 - 0.94 (m, 2H).

[0062] Comparative Example 1

[0063] The cyclopropyl-substituted 2H-benzofuran derivative was prepared according to the technical solution disclosed in Patent WO2022179577, and its synthetic route is as follows:

[0064] .

[0065] I. Preparation of Intermediate I0 The process is as follows:

[0066] Under stirring conditions, add dichloromethane (200 ml), Compound I (40.0 g) and pyridine (22.2 g) to the reaction flask. After cooling the system to 5 °C, dilute Compound III (25.2 g) with dichloromethane (40 ml) and add it to the system. After the addition is complete, warm the system to 20 °C and react for 4 h. Then add purified water (400 ml) to the system, stir for 2 h, and then filter the system to obtain a filter cake. The filter cake is rinsed with purified water and ethanol, drained, and slurried and purified with a mixture of methyl tert-butyl ether (150 ml) and absolute ethanol (50 ml). After filtration and drying, Intermediate I0 (41.1 g) is obtained. The HPLC detection results are as Figure 6 shown, with a purity of 95.6% and a yield of 69.0%. The content of impurity A is 4.4%.

[0067] II. Preparation of Intermediate II The process is as follows:

[0068] Under stirring, add N,N-dimethylacetamide (400 ml), Intermediate I0 prepared above (40 g), Compound II (60.7 g), cesium carbonate (76.7 g) and potassium iodide (1.56 g) to the reaction flask. After the addition is complete, warm the system to 45 °C and react for 16 h. Then cool the reaction system to room temperature, and then add purified water (1.6 L) and ethyl acetate (500 ml) to the reaction system. After stirring and extraction, extract the aqueous phase with ethyl acetate (500 ml) one more time. Combine the ethyl acetate organic phases, wash them successively with purified water (300 ml) and saturated brine (300 ml), and then dry the ethyl acetate with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a red-brown viscous crude product. Then refine the viscous crude product first with dichloromethane and n-heptane, and then use a mixed solution of ethyl acetate and n-heptane for slurry purification to obtain Intermediate II (35.9 g). The HPLC detection results are as Figure 7 shown, with a purity of 95.3% and a yield of 59.1%.

[0069] III. Preparation of cyclopropyl-substituted 2H-benzofuran derivatives. The process is as follows:

[0070] Under room temperature conditions, stir and successively add acetonitrile (350 ml) and Intermediate II obtained above (35.0 g), after stirring and dissolving, 350 ml of a mixed solution of disodium hydrogen phosphate and citric acid with a pH of 3 was added as an acidic hydrolysis solution. After the addition was completed, the reaction solution was heated to 45 °C and reacted for 24 h. After the reaction was detected by liquid phase and ended, the reaction solution was cooled to room temperature, and then ethyl acetate (1.6 L) and purified water (1.2 L) were added. After stirring, the mixture was allowed to stand for liquid separation. The organic phase was washed with purified water (100 ml × 3), and then saturated sodium bicarbonate aqueous solution (400 ml) was added to the organic phase. After stirring, the mixture was allowed to stand for liquid separation, and the lower aqueous phase was retained. Aqueous potassium bisulfate solution with a concentration of 1 M was added to the aqueous phase in batches to adjust its pH to 4, and then it was extracted with ethyl acetate (800 ml × 3). The obtained ethyl acetate solution was dried with anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a concentrate. Then the concentrate was added to acetone (270 ml). After stirring and dissolving, tromethamine (8.51 g) was dissolved in purified water (35 ml) and added to the reaction system. The reaction system was heated to 25 °C and reacted for 16 h. After filtration, a filter cake was obtained. After it was rinsed with acetone (100 ml), it was dried under vacuum to obtain a cyclopropyl-substituted 2H-benzofuran derivative (27.3 g). The HPLC detection results are as Figure 8 shown, with a purity of 96.7% and a yield of 65.1%.

[0071] It can be seen from Example 1 and Comparative Example 1 that by using the preparation method provided by the present invention, the purity and yield of the cyclopropyl-substituted 2H-benzofuran derivative are higher than those of the cyclopropyl-substituted 2H-benzofuran derivative obtained by using the preparation method provided by the comparative example. Moreover, by using the preparation method provided in Example 1, the generation of intermediate impurity A, impurity B, and impurity C is effectively avoided, which is beneficial to improving the quality and safety of the final target compound.

[0072] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some of the technical features. And these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the various 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 as follows: ； It includes the following steps: S100. At a temperature of 0 to 30 °C, add reaction solvent I to the reaction system, and successively add compound I , acid-binding agent I and compound II under stirring, and prepare intermediate I at a temperature of 25 to 35 °C; Among them, the acid-binding agent I is selected from at least one of triethylamine and N,N-diisopropylethylamine; S200. At a temperature of 0 to 30 °C, add reaction solvent II, the intermediate I and acid-binding agent II to the reaction system. Under stirring conditions, after cooling the temperature to 0 to 10 °C, add compound III dropwise to prepare intermediate II ; Among them, the acid-binding agent II is selected from at least one of triethylamine and N,N-diisopropylethylamine; S300. Use the intermediate II to prepare the cyclopropyl-substituted 2H-benzofuran derivative.

2. The method for preparing a cyclopropyl-substituted 2H-benzofuran derivative according to claim 1, characterized in that, The further process of step S100 is as follows: After reacting for 6 ± 0.5 h, water is added to the reaction system. After stirring evenly, it is left to stand, and the aqueous phase is removed to obtain an organic phase. After drying and concentrating under reduced pressure, methyl tert-butyl ether is added, and after stirring and crystallizing for 1 ± 0.5 h, it is filtered and dried to obtain intermediate I; The further process of step S200 is as follows: After reacting for 3 ± 0.5 h, water is added to the reaction system. After stirring evenly, it is left to stand, and the aqueous phase is removed to obtain an organic phase. After concentrating it under reduced pressure, n-heptane and ethyl acetate are added, and after stirring and crystallizing for 2 ± 0.5 h, it is 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 with a pH of 3 are added to the reaction system, and then the temperature is raised to 45 °C. After reacting for 24 ± 1 h, the temperature is lowered to 0 - 30 °C. After extraction and concentration, acetone is added to the reaction system. After stirring and dissolving, a tri(hydroxymethyl)aminomethane solution is added, and then the temperature is raised to 45 ± 0.5 °C. After crystallizing for 16 ± 1 h, the temperature is lowered to 23 ± 0.5 °C, and after holding and stirring for 2 ± 0.5 h, it is filtered to obtain a filter cake, which is dried to obtain the cyclopropyl-substituted 2H-benzofuran derivative.

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

1.

4. The method for preparing a cyclopropyl-substituted 2H-benzofuran derivative according to claim 1, 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.

5. The method for preparing a cyclopropyl-substituted 2H-benzofuran derivative according to claim 4, characterized in that, Both the reaction solvent I and the reaction solvent II are selected from dichloromethane.

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

1.

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

1.

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

1.

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

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