Preparation method of regorafenib intermediate

Abstract

The invention is applicable to the technical field of drug synthesis, and provides a preparation method of a regorafenib intermediate, which comprises the following steps: under the protection of nitrogen, adding N-methyl-4-chloro-2-pyridinecarboxamide, 4-amino-3-fluorophenol, N-methyl pyrrolidone and tetrahydrofuran into a reaction device for mixing, dissolving and clarifying, and heating to 80-90 DEG C; the method comprises the following steps: dissolving potassium tert-butoxide by using N-methyl pyrrolidone to obtain a potassium tert-butoxide solution; and when the internal temperature of the reaction device reaches 80-90 DEG C, quickly adding a potassium tert-butoxide solution for full reaction, and cooling and crystallizing to obtain the regorafenib intermediate. According to the method disclosed by the invention, the contents of process impurities I and II are greatly reduced, the conversion rate and the yield are remarkably improved, the dosage of N-methyl pyrrolidone is reduced, the production cost is reduced, the obtained regorafenib intermediate is high in yield and purity, the product quality strictly meets the standard, and the method is suitable for industrial production. And a technical scheme with economical efficiency and reliability is provided for industrial production.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical synthesis technology, and in particular relates to a method for preparing a regorafenib intermediate. Background Technology

[0002] Regorafenib is a novel oral multi-kinase inhibitor that blocks multiple enzymes that promote tumor growth. It inhibits tumor formation, angiogenesis, and tumor microenvironment formation by acting on multiple kinases in tumor cells, endothelial cells, and peripheral cells. Compared to other monoclonal antibody-targeted therapies for colorectal cancer, regorafenib's small molecule structure allows it to enter the cell membrane, thereby exerting its anti-tumor effect. It is used to treat metastatic colorectal cancer (CRC), gastrointestinal stromal tumors (GIST), and hepatocellular carcinoma.

[0003] In the currently reported methods, the reaction step involving the key intermediate 4-(4-amino-3-fluorophenoxy)-N-methylpyridineamide (Formula 1) is crucial for the synthesis of regorafenib. The purity and yield of the compound in Formula 1 directly affect the purity and yield of the prepared regorafenib. Therefore, the synthetic study of Formula 1 is very important, and its specific structural formula is as follows:

[0004]

[0005] The commonly used method is to first protect the amino group of 4-amino-3-fluorophenol (Formula 2) to reduce side reactions and impurity content. However, this method adds amino protection and deprotection steps, increasing reaction steps and post-processing operations, thus increasing production costs. Currently, there are also preparation methods that do not require amino protection, but these methods tend to generate difficult-to-remove process impurities when synthesizing Formula 1, requiring multiple recrystallization purifications to obtain a qualified Formula 1, ultimately resulting in a low yield for this step. Summary of the Invention

[0006] The purpose of this application is to provide a method for preparing regorafenib intermediates, which aims to solve the problems of excessive N-methylpyrrolidone usage, high impurity content, and cumbersome and time-consuming purification steps in the existing synthesis process of regorafenib intermediates (Formula 1).

[0007] The embodiments of this application are implemented as follows: a method for preparing a regorafenib intermediate includes:

[0008] Under nitrogen protection, N-methyl-4-chloro-2-pyridinecarboxamide, 4-amino-3-fluorophenol, N-methylpyrrolidone, and tetrahydrofuran were added to the reaction apparatus, mixed and dissolved, and then heated to 80-90°C.

[0009] Under nitrogen protection, potassium tert-butoxide was dissolved in N-methylpyrrolidone to obtain a potassium tert-butoxide solution;

[0010] When the internal temperature of the reaction apparatus reaches 80-90℃, the potassium tert-butoxide solution is quickly added to allow for a full reaction. After cooling and crystallization, the regorafenib intermediate is obtained.

[0011] Preferably, the mass ratio of N-methyl-4-chloro-2-pyridinecarboxamide, tetrahydrofuran and N-methylpyrrolidone is 1:(0.09-2.67):6.18.

[0012] Preferably, the potassium tert-butoxide solution is added within 4-6 minutes.

[0013] The method for preparing regorafenib intermediates provided in this application achieves multiple technological breakthroughs through innovative process design: The raw materials are dissolved in a mixed solvent system of N-methylpyrrolidone and a small amount of tetrahydrofuran, where tetrahydrofuran acts as an inhibitor to effectively reduce the generation of reaction impurities. Simultaneously, potassium tert-butoxide is dissolved separately and rapidly added to the reaction system. By precisely controlling the dissolution temperature of the raw materials, the molar ratio of potassium tert-butoxide to the raw materials, and the feeding rate, a synergistic mechanism for impurity inhibition and reaction efficiency improvement is constructed. This method not only significantly reduces the content of process impurities I and II, significantly improving the conversion rate and yield of the raw materials in Formula 1, but also reduces the amount of N-methylpyrrolidone used by optimizing the solvent ratio, thus lowering production costs. The obtained regorafenib intermediate has high yield and high purity, and the product quality strictly meets standards. Furthermore, this preparation method has a simple process route, is convenient to operate, and the post-processing and purification procedures are simple and efficient. While achieving process optimization and quality improvement, it provides an economical and reliable technical solution for industrial production. Attached Figure Description

[0014] Figure 1 This is an HPLC chromatogram of the regorafenib intermediate provided in Example 1 of this application;

[0015] Figure 2 This is an HPLC chromatogram of the regorafenib intermediate provided in Example 2 of this application;

[0016] Figure 3 This is an HPLC chromatogram of the regorafenib intermediate provided in Example 3 of this application;

[0017] Figure 4 This is an HPLC chromatogram of the regorafenib intermediate provided in Example 4 of this application;

[0018] Figure 5 This is an HPLC chromatogram of the regorafenib intermediate provided in Example 5 of this application;

[0019] Figure 6 This is an HPLC chromatogram of the regorafenib intermediate provided in Example 6 of this application;

[0020] Figure 7 This is the HPLC chromatogram of the regorafenib intermediate provided in Comparative Example 1 of this application;

[0021] Figure 8 This is an HPLC chromatogram of the regorafenib intermediate provided in Comparative Example 2 of this application. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of this application clearer, the following detailed description is provided in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the scope of this application.

[0023] To address the problems of high N-methylpyrrolidone usage, high impurity content, and cumbersome and time-consuming purification steps in existing synthesis processes of regorafenib intermediates (Formula 1), this application provides a method for preparing regorafenib intermediates. This method achieves multiple technological breakthroughs through innovative process design: The raw materials are dissolved in a mixed solvent system of N-methylpyrrolidone and a small amount of tetrahydrofuran, where tetrahydrofuran acts as an inhibitor to effectively reduce the generation of reaction impurities. Simultaneously, potassium tert-butoxide is dissolved separately and rapidly added to the reaction system. By precisely controlling the raw material dissolution temperature, the molar ratio of potassium tert-butoxide to the raw materials, and the addition rate, a synergistic mechanism for impurity inhibition and reaction efficiency improvement is constructed. This method not only significantly reduces the content of process impurities I and II, significantly improving the conversion rate and yield of the raw materials in Formula 1, but also reduces the amount of N-methylpyrrolidone used by optimizing the solvent ratio, thus lowering production costs. The resulting regorafenib intermediate has high yield and high purity, and the product quality strictly meets standards. Furthermore, the preparation method has a simple process route and is easy to operate. The post-processing and purification process is simple and efficient. While achieving process optimization and quality improvement, it provides an economical and reliable technical solution for industrial production.

[0024] Specifically, the present application provides a method for preparing a regorafenib intermediate, comprising:

[0025] Under nitrogen protection, N-methyl-4-chloro-2-pyridinecarboxamide (Formula 3), 4-amino-3-fluorophenol (Formula 2), N-methylpyrrolidone, and tetrahydrofuran are added to the reaction apparatus, mixed and dissolved, and then heated to 80-90°C.

[0026] Under nitrogen protection, potassium tert-butoxide was dissolved in N-methylpyrrolidone to obtain a potassium tert-butoxide solution;

[0027] When the internal temperature of the reaction apparatus reaches 80-90℃, the potassium tert-butoxide solution is quickly added to allow for a full reaction. After cooling and crystallization, the regorafenib intermediate (Formula 1) is obtained.

[0028] The synthetic route is shown below:

[0029]

[0030] In the overall reaction system, the ratio of N-methyl-4-chloro-2-pyridinecarboxamide, tetrahydrofuran, and N-methylpyrrolidone (the sum of the amounts of N-methylpyrrolidone used in all steps) has a significant impact on the formation of impurity I and impurity II. Experiments have determined that the preferred mass ratio of N-methyl-4-chloro-2-pyridinecarboxamide, tetrahydrofuran, and N-methylpyrrolidone is 1:(0.09-2.67):6.18; more preferably, the mass ratio is 1:(0.09-0.89):6.18. Notably, this application innovatively uses tetrahydrofuran as an inhibitor to reduce the generation of reaction impurities, while simultaneously reducing the amount of N-methylpyrrolidone used, ultimately improving product yield and purity and reducing production costs.

[0031] The structural formulas of impurity I and impurity II are shown below:

[0032]

[0033] The temperature of the reaction system should be maintained between 80-90℃. If the temperature is below 80℃, the raw materials will not react completely; if the temperature is above 90℃, a large number of impurities will be generated.

[0034] The potassium tert-butoxide solution should be added within 4-6 minutes. Adding it too slowly will reduce the conversion rate in the reaction mixture and significantly increase the amount of impurity II.

[0035] When the content of potassium tert-butoxide is too low, it will lead to an increase in raw material residue. Considering the overall cost, the preferred molar ratio of N-methyl-4-chloro-2-pyridinecarboxamide to potassium tert-butoxide is 1:(1.15-1.3).

[0036] Optionally, when the internal temperature of the reaction apparatus reaches 80-90°C, the potassium tert-butoxide solution is rapidly added to allow for a complete reaction. The reaction is then cooled and crystallized to obtain the regorafenib intermediate. This step includes:

[0037] When the internal temperature of the reaction apparatus reaches 80-90℃, potassium tert-butoxide solution is quickly added and reacted at 80-90℃ for 4 hours. After the reaction is completed, the temperature is lowered to 60±5℃, and the mixture is subjected to crystallization treatment with glacial acetic acid aqueous solution, purified water and n-heptane in sequence to obtain regorafenib intermediate.

[0038] Optionally, the crystallization process involves sequentially passing the solution of glacial acetic acid, purified water, and n-heptane, specifically including:

[0039] The reaction was quenched and crystallized by glacial acetic acid aqueous solution at 60±5℃. Then, purified water and n-heptane were added at 30±5℃ to crystallize for 0.5h. The temperature was lowered to 0~10℃ and crystallized for 4±2h. The mixture was filtered, the filter cake was washed with purified water, and the filter cake was collected and dried to obtain regorafenib intermediate.

[0040] Optionally, in order to ensure the conversion rate of raw materials, based on existing technology, the molar ratio of 4-amino-3-fluorophenol to N-methyl-4-chloro-2-pyridinecarboxamide can be determined to be no less than 1.05 times.

[0041] The preparation method of regorafenib intermediates is described in detail below with specific examples. Unless otherwise specified, conditions in the following examples were performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are all commercially available products.

[0042] Example 1:

[0043] Under nitrogen protection, N-methylpyrrolidone ① (30.90 g) and tetrahydrofuran (26.70 g) were added to the reaction flask, followed by compound 3 (10.00 g, 58.62 mmol, 1.00 eq) and compound 2 (7.45 g, 58.62 mmol, 1.00 eq) in sequence. The mixture was stirred and the temperature was slowly raised to 80-90 °C. Potassium tert-butoxide (7.56 g, 67.37 mmol, 1.15 eq) was dissolved in N-methylpyrrolidone ② (30.90 g) and set aside. When the internal temperature of the reaction flask reached 80-90 °C, the potassium tert-butoxide solution was added to the reaction system over 4-6 minutes. The reaction was continued at 80-90 °C. After the reaction was complete, the reaction solution was transferred to a suitable reaction flask, cooled to 60±5 °C, and a prepared aqueous solution of glacial acetic acid (7.00 g of glacial acetic acid and 13 g of purified water) was added. The reaction was quenched and crystallized by adding 3.00 g of purified water (176.00 g) at 30 ± 5 °C, followed by n-heptane (10.20 g). The mixture was stirred at 25 ± 5 °C for 0.5 h to allow crystallization. The temperature was then lowered to 0–10 °C and maintained for 4 ± 2 h to allow crystallization. The mixture was filtered, and the filter cake was washed with purified water (60.00 g). The filter cake was collected and dried to obtain 14.51 g of reddish-brown powder (compound formula 1), with a yield of 94.68% and an HPLC purity of 97.03%. (See attached table). Figure 1 .

[0044] Example 2:

[0045] Under nitrogen protection, N-methylpyrrolidone ① (92.70 g) and tetrahydrofuran (53.40 g) were added to the reaction flask, followed by compound 3 (30.00 g, 0.176 mol, 1.00 eq) and compound 2 (22.35 g, 0.176 mol, 1.00 eq) in sequence. Stirring was started, and the temperature was slowly raised to 80-90 °C. Potassium tert-butoxide (22.69 g, 0.202 mol, 1.15 eq) was dissolved in N-methylpyrrolidone ② (92.70 g) and set aside. When the internal temperature of the reaction flask reached 80-90 °C, the potassium tert-butoxide solution was added to the reaction system over 4-6 minutes. The reaction was carried out at an internal temperature of 80-90 °C. After the reaction was completed, the reaction solution was transferred to a suitable reaction flask, cooled to 60±5 °C, and a prepared aqueous solution of glacial acetic acid (21.00 g of glacial acetic acid and 39 g of purified water) was added. The reaction was quenched and crystallized by adding 9.00 g of purified water (528.00 g) at 30 ± 5 °C, followed by n-heptane (30.60 g). The mixture was stirred at 25 ± 5 °C for 0.5 h to allow crystallization. The temperature was then lowered to 0–10 °C and maintained for 4 ± 2 h to allow crystallization. The mixture was filtered, and the filter cake was washed with purified water (180.00 g). The filter cake was collected and dried to obtain 43.71 g of reddish-brown powder (compound formula 1), with a yield of 95.14% and an HPLC purity of 98.32%. (See figure below) Figure 2 .

[0046] Example 3:

[0047] Under nitrogen protection, N-methylpyrrolidone ① (154.50 g) and tetrahydrofuran (44.50 g) were added to a reaction flask. Then, compound 3 (50.00 g, 0.293 mol, 1.00 eq) and compound 2 (37.25 g, 0.293 mol, 1.00 eq) were added sequentially. The mixture was stirred and the temperature was slowly raised to 80-90 °C. Potassium tert-butoxide (37.80 g, 0.337 mol, 1.15 eq) was dissolved in N-methylpyrrolidone ② (154.50 g) and set aside. When the internal temperature of the reaction flask reached 80-90 °C, the potassium tert-butoxide solution was added to the reaction system over 4-6 minutes. The reaction was carried out at an internal temperature of 80-90 °C. After the reaction was completed, the reaction solution was transferred to a suitable reaction flask and cooled to 60±5 °C. A prepared aqueous solution of glacial acetic acid (35.00 g of glacial acetic acid and 6 g of purified water) was added. The reaction was quenched and crystallized by adding 65.00 g of purified water (880.00 g) at 30 ± 5 °C, followed by n-heptane (51.00 g). The mixture was stirred at 25 ± 5 °C for 0.5 h to allow crystallization. The temperature was then lowered to 0–10 °C and maintained at this temperature for 4 ± 2 h to allow crystallization. The mixture was filtered, and the filter cake was washed with purified water (300.00 g). The filter cake was collected and dried to obtain 72.92 g of reddish-brown powder (compound formula 1), with a yield of 95.23% and an HPLC purity of 99.04%. (See attached table). Figure 3 .

[0048] Example 4:

[0049] Under nitrogen protection, N-methylpyrrolidone ① (154.50 g) and tetrahydrofuran (22.25 g) were added to a reaction flask. Then, compound 3 (50.00 g, 0.293 mol, 1.00 eq) and compound 2 (37.25 g, 0.293 mol, 1.00 eq) were added sequentially. The mixture was stirred and the temperature was slowly raised to 80-90 °C. Potassium tert-butoxide (37.80 g, 0.337 mol, 1.15 eq) was dissolved in N-methylpyrrolidone ② (154.50 g) and set aside. When the internal temperature of the reaction flask reached 80-90 °C, the potassium tert-butoxide solution was added to the reaction system over 4-6 minutes. The reaction was carried out at an internal temperature of 80-90 °C. After the reaction was completed, the reaction solution was transferred to a suitable reaction flask and cooled to 60±5 °C. A prepared aqueous solution of glacial acetic acid (35.00 g of glacial acetic acid and 6 g of purified water) was added. The reaction was quenched and crystallized by adding 65.00 g of purified water (880.00 g) at 30 ± 5 °C, followed by n-heptane (51.00 g). The mixture was stirred at 25 ± 5 °C for 0.5 h to allow crystallization. The temperature was then lowered to 0–10 °C and maintained for 4 ± 2 h to allow crystallization. The mixture was filtered, and the filter cake was washed with purified water (300.00 g). The filter cake was collected and dried to obtain 72.59 g of reddish-brown powder (compound formula 1), with a yield of 94.82% and an HPLC purity of 99.35%. Figure 4 .

[0050] Example 5:

[0051] Under nitrogen protection, N-methylpyrrolidone ① (154.50 g) and tetrahydrofuran (4.45 g) were added to a reaction flask, followed by compound 3 (50.00 g, 0.293 mol, 1.00 eq) and compound 2 (37.25 g, 0.293 mol, 1.00 eq) in sequence. Stirring was started, and the temperature was slowly raised to 80-90 °C. Potassium tert-butoxide (37.80 g, 0.337 mol, 1.15 eq) was dissolved in N-methylpyrrolidone ② (154.50 g) and set aside. When the internal temperature of the reaction flask reached 80-90 °C, the potassium tert-butoxide solution was added to the reaction system over 4-6 minutes. The reaction was carried out at an internal temperature of 80-90 °C. After the reaction was complete, the reaction solution was transferred to a suitable reaction flask, cooled to 60±5 °C, and a prepared aqueous solution of glacial acetic acid (35.00 g of glacial acetic acid and 6 g of purified water) was added. The reaction was quenched and crystallized by adding 65.00 g of purified water (880.00 g) at 30±5℃, followed by n-heptane (51.00 g). The mixture was stirred at 25±5℃ for 0.5 h to allow crystallization. The temperature was then lowered to 0–10℃ and maintained for 4±2 h to allow crystallization. The mixture was filtered, and the filter cake was washed with purified water (300.00 g). The filter cake was collected and dried to obtain 72.49 g of reddish-brown powder (compound formula 1), with a yield of 94.67% and an HPLC purity of 99.30%. Figure 5 .

[0052] The yields and purity of the regorafenib intermediates obtained in Examples 1-5, as well as the experimental data for impurity I and impurity II, are shown in Table 1 below:

[0053] Table 1

[0054]

[0055]

[0056] In the early stages of research and development, this application also conducted a series of experiments on the feeding time of potassium tert-butoxide solution, as detailed below:

[0057] Example 6:

[0058] Under nitrogen protection, N-methylpyrrolidone ① (30.90 g) and tetrahydrofuran (4.45 g) were added to the reaction flask, followed by compound 3 (10.00 g, 58.62 mmol, 1.00 eq) and compound 2 (7.45 g, 58.62 mmol, 1.00 eq) sequentially. Stirring was started, and the temperature was slowly increased to 80-90 °C. Potassium tert-butoxide (7.56 g, 67.37 mmol, 1.15 eq) was dissolved in N-methylpyrrolidone ② (30.90 g) and set aside. When the internal temperature of the reaction flask reached 80-90 °C, the potassium tert-butoxide solution was added to the reaction system over 4-6 minutes. The reaction was carried out at an internal temperature of 80-90 °C. After the reaction was completed, the reaction solution was sent to HPLC control. HPLC analysis showed a product conversion rate of 93.17%. Figure 6 .

[0059] Comparative Example 1:

[0060] Under nitrogen protection, N-methylpyrrolidone ① (30.90 g) and tetrahydrofuran (4.45 g) were added to the reaction flask, followed by compound 3 (10.00 g, 58.62 mmol, 1.00 eq) and compound 2 (7.45 g, 58.62 mmol, 1.00 eq) sequentially. Stirring was started, and the temperature was slowly increased to 80-90 °C. Potassium tert-butoxide (7.56 g, 67.37 mmol, 1.15 eq) was dissolved in N-methylpyrrolidone ② (30.90 g) and set aside. When the internal temperature of the reaction flask reached 80-90 °C, the potassium tert-butoxide solution was added to the reaction system over 10 min. The reaction was continued at 80-90 °C. After the reaction was complete, the reaction solution was sent to HPLC for analysis. HPLC analysis showed a product conversion rate of 60.59%. Figure 7 .

[0061] Comparative Example 2:

[0062] Under nitrogen protection, N-methylpyrrolidone ① (30.90 g) and tetrahydrofuran (4.45 g) were added to the reaction flask, followed by compound 3 (10.00 g, 58.62 mmol, 1.00 eq) and compound 2 (7.45 g, 58.62 mmol, 1.00 eq) sequentially. The mixture was stirred and the temperature was slowly raised to 80-90 °C. Potassium tert-butoxide (7.56 g, 67.37 mmol, 1.15 eq) was dissolved in N-methylpyrrolidone ② (30.90 g) and set aside. When the internal temperature of the reaction flask reached 80-90 °C, the potassium tert-butoxide solution was added to the reaction system after 30 min. The reaction was continued at 80-90 °C. After the reaction was complete, the reaction solution was sent to HPLC for analysis. HPLC analysis showed a product conversion rate of 55.66%. Figure 8 .

[0063] Table 2 below shows the experimental data for controlled conversion rate, impurity I, and impurity II in the reaction solutions corresponding to Examples 6 and Comparative Examples 1-2:

[0064] Table 2

[0065] Serial Number Conversion rate controlled in reaction solution Impurity I Impurity II Potassium tert-butoxide solution dropping time Example 6 93.17％ 0.281％ 0.120％ 4-6 min Comparative Example 1 60.59％ 0.197％ 7.914％ 10min Comparative Example 2 55.66％ 0.290％ 11.152％ 30min

[0066] In summary, the method for preparing regorafenib intermediates provided in this application achieves multiple technological breakthroughs through innovative process design: The raw materials are dissolved in a mixed solvent system of N-methylpyrrolidone and a small amount of tetrahydrofuran, where tetrahydrofuran acts as an inhibitor to effectively reduce the generation of reaction impurities. Simultaneously, potassium tert-butoxide is dissolved separately and rapidly added to the reaction system. By precisely controlling the raw material dissolution temperature, the molar ratio of potassium tert-butoxide to the raw materials, and the feeding rate, a synergistic mechanism for impurity inhibition and reaction efficiency improvement is constructed. This method not only significantly reduces the content of process impurities I and II, significantly improving the conversion rate and yield of the raw materials in Formula 1, but also reduces the amount of N-methylpyrrolidone used by optimizing the solvent ratio, thus lowering production costs. The obtained regorafenib intermediate has high yield and high purity, and the product quality strictly meets standards. Furthermore, this preparation method has a simple process route, is convenient to operate, and the post-processing and purification procedures are simple and efficient. While achieving process optimization and quality improvement, it provides an economical and reliable technical solution for industrial production.

[0067] The embodiments described above are merely illustrative of several implementation methods of this application, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of this patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims.

[0068] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A method for preparing a regorafenib intermediate, characterized in that, include: Under nitrogen protection, N-methyl-4-chloro-2-pyridinecarboxamide, 4-amino-3-fluorophenol, N-methylpyrrolidone, and tetrahydrofuran were added to the reaction apparatus, mixed and dissolved, and then heated to 80-90°C. Under nitrogen protection, potassium tert-butoxide was dissolved in N-methylpyrrolidone to obtain a potassium tert-butoxide solution; When the internal temperature of the reaction apparatus reaches 80-90℃, the potassium tert-butoxide solution is quickly added to allow for a full reaction. After cooling and crystallization, the regorafenib intermediate is obtained.

2. The method for preparing the regorafenib intermediate according to claim 1, characterized in that, The mass ratio of N-methyl-4-chloro-2-pyridinecarboxamide, tetrahydrofuran and N-methylpyrrolidone is 1:(0.09-2.67):6.

18.

3. The method for preparing the regorafenib intermediate according to claim 2, characterized in that, The mass ratio of N-methyl-4-chloro-2-pyridinecarboxamide, tetrahydrofuran and N-methylpyrrolidone is 1:(0.09-0.89):6.

18.

4. The method for preparing the regorafenib intermediate according to claim 1, characterized in that, Add the potassium tert-butoxide solution within 4-6 minutes.

5. The method for preparing the regorafenib intermediate according to claim 1, characterized in that, The molar ratio of N-methyl-4-chloro-2-pyridinecarboxamide to potassium tert-butoxide is 1:(1.15-1.3).

6. The method for preparing the regorafenib intermediate according to claim 1, characterized in that, When the internal temperature of the reaction apparatus reaches 80-90℃, the potassium tert-butoxide solution is rapidly added to allow for a complete reaction. The process, followed by cooling and crystallization, yields the regorafenib intermediate. The steps include: When the internal temperature of the reaction apparatus reaches 80-90℃, potassium tert-butoxide solution is quickly added and reacted at 80-90℃ for 4 hours. After the reaction is completed, the temperature is lowered to 60±5℃, and the mixture is subjected to crystallization treatment with glacial acetic acid aqueous solution, purified water and n-heptane in sequence to obtain regorafenib intermediate.

7. The method for preparing the regorafenib intermediate according to claim 5, characterized in that, The crystallization process, involving sequential treatment with glacial acetic acid aqueous solution, purified water, and n-heptane, specifically includes: The reaction was quenched and crystallized by glacial acetic acid aqueous solution at 60±5℃. Then, purified water and n-heptane were added at 30±5℃ to crystallize for 0.5h. The temperature was lowered to 0~10℃ and crystallized for 4±2h. The mixture was filtered, the filter cake was washed with purified water, and the filter cake was collected and dried to obtain regorafenib intermediate.

8. The method for preparing the regorafenib intermediate according to claim 5, characterized in that, The molar ratio of 4-amino-3-fluorophenol to N-methyl-4-chloro-2-pyridinecarboxamide is not less than 1.05.

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