Process for the preparation of fruquidone and intermediates thereof

Abstract

The application provides a preparation method of fuqin tini and intermediates thereof, which is economical, reduces the danger degree of industrial production, is stable and controllable in a reaction process, has higher safety, and is more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to the preparation method of fruquintinib and fruquintinib intermediates. Background Technology

[0002] Fruquintinib, chemically named 6-((6,7-dimethoxyquinazolin-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide, with its chemical structure shown in Formula I, is a novel, highly effective, selective VEGFR inhibitor primarily used for the treatment of cancers such as colorectal cancer, non-small cell lung cancer, and gastric cancer.

[0003] Formula I

[0004] Fruquintinib was independently developed by Hutchison MediPharma and approved for marketing by the National Medical Products Administration (NMPA) in September 2018 as a Class 1.1 new drug for the treatment of metastatic colorectal cancer (mCRC). Its brand name is Aiyoute. ® The marketed dosage form is capsules. In January 2023, Hutchison MediPharma signed an overseas licensing agreement with Takeda Pharmaceutical Company of Japan. In November 2023, fruquintinib received marketing approval from the U.S. Food and Drug Administration (FDA) through an application by Takeda Pharmaceutical Company, under the brand name FRUZAQLA. ® .

[0005] WO2009 / 137797 discloses the compound fruquintinib, its preparation method, pharmaceutical compositions thereof, and its use for treating diseases related to angiogenesis disorders. CN101575333A discloses the compound fruquintinib and its preparation method. The key to the synthesis of fruquintinib lies in the synthesis of the intermediate 6-hydroxy-N,2-dimethylbenzofuran-3-carboxamide.

[0006] The report in WO2005 / 063739 (or CN1890234A) states that in the preparation of 6-hydroxy-N,2-dimethylbenzofuran-3-carboxamide, the monomethylamine used is a gas, and the solution formed after dissolving in tetrahydrofuran is extremely unstable, which increases the difficulty of the process and brings potential dangers.

[0007] WO2007 / 066181 reported that during the preparation of 2-methyl-3-formylchloro-6-methoxybenzofuran, a large amount of sodium sulfide was generated, which had a very unpleasant odor. This led to the need for post-processing of the reaction to use an excess of sodium hypochlorite solution to convert it into sodium sulfate. However, the use of strong oxidants such as sodium hypochlorite would cause the product to be oxidized and decomposed, and the yield of this step was only 53% (and the purity was 92%).

[0008] The preparation of 6-hydroxy-N,2-dimethylbenzofuran-3-carboxamide reported in CN104628686A involves carboxylation, chlorination, and amidation of 2-methyl-6-methoxybenzofuran, resulting in a long and uneconomical process. Furthermore, the reaction of monomethylamine hydrochloride with solid sodium hydroxide releases monomethylamine gas, a chemical change that generates significant heat and the highly explosive gas monomethylamine, posing a major challenge to industrial production. This method also presents substantial safety risks.

[0009] In summary, given the numerous shortcomings of current methods for preparing fruquintinib in terms of process safety, low yield, and poor economic efficiency, finding a process route that is stable and controllable, yields higher, and is more suitable for industrial production of fruquintinib remains a problem that needs to be solved. Summary of the Invention

[0010] To address the aforementioned problems in the existing technology, the present invention aims to provide a method for preparing a key intermediate of fruquintinib and a method for synthesizing fruquintinib using the intermediate. This method is economical, has a high yield, is simple to operate, and the reaction process is safer and more controllable, making it more suitable for industrial production.

[0011] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0012] A method for preparing fruquintinib, comprising the following steps:

[0013] (1) Add compound SM-1, formamidin or its salt to solvent A, and control the temperature T. A After the reaction was completed, the intermediate compound I-1 was obtained through post-processing.

[0014] (2) Add compound I-1 and solvent B to thionyl chloride and control the temperature T. B After the reaction was completed, the intermediate compound I-2 was obtained through post-processing.

[0015] (3) Add oxalyl chloride and aluminum trichloride to solvent Ca, and after the reaction is controlled at temperature, add compound SM-2 and control the temperature T. C1 After reaction ① is completed, compound II is obtained through post-treatment; methylamine or its salt and base C are added to the reaction system in solvent Cb, and the temperature is maintained at T. C2 After reaction ② is completed, intermediate compound I-3 is obtained through post-processing and purification;

[0016] (4) Add compound I-3 and boron tribromide to solvent D, and control the temperature T. D After the reaction was completed, the intermediate compound I-4 was obtained through post-processing.

[0017] (5) Add compound I-2, compound I-4, and base E to solvent E, and control the temperature T. E After the reaction was completed, compound I was obtained through post-treatment.

[0018] Preferably, solvent A in step (1) is selected from one or more of toluene, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, and is preferably toluene.

[0019] Preferably, the temperature control T in step (1) A The temperature is 90–110℃, preferably 95–105℃.

[0020] Preferably, the reaction time in step (1) is 1 to 10 hours, and more preferably 6 to 9 hours.

[0021] Preferably, the molar ratio of compound SM-1 to formamidin or its salt in step (1) is 1:1~2, more preferably 1:1.2~1.5.

[0022] Preferably, the formamidine or its salt mentioned in step (1) is one or more of formamidine, formamidine hydrochloride, and formamidine acetate, preferably formamidine acetate. Formamidine acetate is also known as formamidine acetate.

[0023] In a preferred embodiment, after the reaction in step (1) is completed, a post-processing operation is required, specifically: the reaction solution is cooled to 10±5℃, purified water is added and stirred to precipitate crystals, centrifuged, and dried to obtain compound I-1.

[0024] Preferably, the solvent B in step (2) is selected from one or more of N,N-dimethylformamide or N,N-dimethylacetamide, and is more preferably N,N-dimethylformamide.

[0025] Preferably, the temperature control T in step (2) B The temperature range is 60–100℃, preferably 85–95℃.

[0026] Preferably, the reaction time in step (2) is 2 to 5 hours, and more preferably 3 to 4 hours.

[0027] Preferably, the molar ratio of compound I-1 to thionyl chloride in step (2) is 1:5~15, more preferably 1:10~15.

[0028] In a preferred embodiment, after the reaction in step (2) is completed, a post-processing operation is required, specifically: the reaction solution is cooled to 10±5℃, ethyl acetate is added and stirred to precipitate crystals, centrifuged, and dried to obtain compound I-2.

[0029] Preferably, the methylamine or its salt in step (3) is selected from one or more of aqueous methylamine solution, methylamine alcohol solution, methylamine tetrahydrofuran solution, methylamine hydrochloride or methylamine sulfate, and is preferably methylamine hydrochloride.

[0030] Preferably, the base C in step (3) is selected from one or more of potassium hydroxide, sodium hydroxide, potassium hydroxide aqueous solution or sodium hydroxide aqueous solution, preferably sodium hydroxide aqueous solution.

[0031] Preferably, the solvent Ca in step (3) is selected from one or more of dichloromethane, tetrahydrofuran or ethyl acetate, and is preferably dichloromethane.

[0032] Preferably, the solvent Cb in step (3) is selected from one or more of dichloromethane, tetrahydrofuran or ethyl acetate, and is preferably dichloromethane.

[0033] Preferably, the temperature control T in step (3) C1 The temperature range is 15–35℃, preferably 20–30℃.

[0034] Preferably, the reaction time in step (3) is 6 to 9 hours, more preferably 7 to 8 hours.

[0035] Preferably, the temperature control T in step (3) C2 The temperature range is 5–20℃, preferably 5–15℃.

[0036] Preferably, the reaction time in step (3) is 3 to 6 hours, and more preferably 4 to 5 hours.

[0037] Preferably, the molar ratio of compound SM-2 in step (3) to oxalyl chloride, aluminum trichloride, methylamine or its salt, and base C is 1:2.0-3.0:2.0-3.0:8.0-10.0:8.0-10.0, and more preferably 1:2.0-2.5:2.0-2.5:9.0-10.0:9.0-10.0.

[0038] In a preferred embodiment, after step (3) reaction ① is completed, a post-processing operation is required, specifically: add purified water to the reaction solution and stir. Under nitrogen protection conditions, let it stand and separate the liquids. Concentrate the obtained organic phase to dryness to obtain intermediate compound II.

[0039] In a preferred embodiment, after reaction ② in step (3) is completed, post-processing and purification are required, specifically: the reaction solution is concentrated to remove dichloromethane from the system. After concentration, methyl tert-butyl ether is added to the residue for purification to obtain intermediate compound I-3.

[0040] In a preferred embodiment, step (3) is a one-pot process.

[0041] Preferably, the solvent D in step (4) is selected from one or more of dichloromethane, tetrahydrofuran or ethyl acetate, and is preferably dichloromethane.

[0042] Preferably, the temperature control T in step (4) D The temperature range is 5–30℃, preferably 5–15℃.

[0043] Preferably, the reaction time in step (4) is 3 to 6 hours, and more preferably 4 to 5 hours.

[0044] Preferably, the molar ratio of compound I-3 to boron tribromide in step (4) is 1:2~5, more preferably 1:2~3.

[0045] In a preferred embodiment, after the reaction in step (4) is completed, post-processing is required, specifically: add purified water to the reaction solution, control the temperature at 5±5℃, keep the reaction at this temperature for 2 h, centrifuge, and dry to obtain compound I-4.

[0046] Preferably, the base E mentioned in step (5) is selected from one or more of diisopropylethylamine, potassium carbonate, cesium carbonate or sodium carbonate, and is preferably potassium carbonate.

[0047] Preferably, the solvent E in step (5) is selected from one or more of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, dimethyl sulfoxide or tetrahydrofuran, and is preferably acetonitrile.

[0048] Preferably, the temperature control T in step (5) E The temperature should be 60–70°C, preferably the reflux temperature.

[0049] Preferably, the reaction time in step (5) is 14 to 17 hours, and more preferably 15 to 16 hours.

[0050] Preferably, the molar ratio of compound I-2 to compound I-4 in step (5) is 1:1 to 2, and more preferably 1:1 to 1.5.

[0051] In a preferred embodiment, after the reaction in step (5) is completed, a post-processing operation is required, specifically: the filter cake and purified water are added to the reaction vessel, the temperature is controlled at 25±5℃, the reaction is kept at this temperature for 2 hours, centrifuged, and dried to obtain compound I.

[0052] The synthesis route is as follows:

[0053] .

[0054] The present invention has at least the following beneficial effects:

[0055] This invention provides a novel method for preparing fruquintinib (I). This method employs a one-pot process to prepare compound II during the preparation of key intermediate compounds I-4, resulting in a simple and economical process. This process effectively avoids the use of methylaminetetrahydrofuran solution, making the reaction safer and reducing the risks associated with industrial production. In summary, the preparation method provided by this invention is economical, the reaction process is stable and controllable, and it offers higher safety, making it more suitable for industrial production. Detailed Implementation

[0056] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0057] Example 1: Preparation of intermediate compound I-1

[0058] 2-Amino-4,5-dimethoxybenzoic acid (SM-1, 2.50 kg), formamidin acetate (1.72 kg), and toluene (10.92 kg) were added to a 50 L reactor. After the addition was complete, stirring was started, and the reaction system was heated to 100±5℃ and maintained at 100±5℃ for 8 h. After the reaction was completed, purified water (25 kg) was slowly added to the 50 L reactor. After the addition was complete, the mixture was stirred at 10±5℃ for 2 h to induce crystallization. After the predetermined time, the mixture was centrifuged and dried to obtain intermediate compound I-1 (yield > 90%, purity > 98%).

[0059] Example 2 Preparation of intermediate compound I-2

[0060] Compound I-1 (2.5 kg), thionyl chloride (20.39 kg), and N,N-dimethylformamide (0.5 kg) were added to a 50 L reactor. After the addition was complete, stirring was started, and the reaction system was heated to 90 ± 5 °C and stirred for 4 h. After the reaction was completed, the reaction system was cooled to 10 ± 5 °C, and ethyl acetate (22.56 kg) was slowly added to the 50 L reactor. After the addition was complete, the temperature was maintained at 10 ± 5 °C and stirred to induce crystallization for 1 h. After the predetermined time, the mixture was centrifuged and dried to obtain intermediate compound I-2 (yield greater than 92%).

[0061] Example 3 Preparation of intermediate compound I-3

[0062] Step 1, Preparation of Compound II:

[0063] Dichloromethane (66 kg) and aluminum trichloride (5.15 kg) were added to a 180 L reactor. After the addition was complete, the reaction system was cooled to 10 ± 5 °C. At the predetermined temperature, oxaloyl chloride (4.90 kg) was added dropwise to the 180 L reactor. After the addition was complete, the temperature was maintained at 10 ± 5 °C for 2 hours. At the predetermined reaction time, a solution of 6-methoxy-2-methylbenzofuran (SM-2, 2.5 kg) / dichloromethane (16.5 kg) was added dropwise to the 180 L reactor. After the addition was complete, the temperature was maintained at 25 ± 5 °C for 8 hours. After the reaction was complete, purified water (25 kg) was added to a 200 L reactor. Stirring was started, and under nitrogen protection, the reaction solution was slowly added to the 200 L reactor. After the addition was complete, the mixture was allowed to stand and separated. The resulting organic phase was concentrated to dryness.

[0064] The second step is the preparation of compound I-3:

[0065] The residue obtained in the first step was dissolved in dichloromethane (33.15 kg), and the solution was transferred to a 50 L reactor. After the transfer was complete, water (12.5 kg) and methylamine hydrochloride (10.43 kg) were added. A prepared sodium hydroxide aqueous solution (sodium hydroxide dissolved in 12.5 kg of purified water) was added dropwise to the 50 L reactor, with the temperature controlled at 10 ± 5 °C during the addition. The reaction was carried out at 10 ± 5 °C with stirring for 5 h. After the reaction was complete, the dichloromethane in the system was removed by concentration. After concentration, methyl tert-butyl ether (18.5 kg) was added to the residue, and the reaction was carried out at 20–30 °C with stirring for 2 h. Centrifugation yielded intermediate compound I-3 (yield 85%, purity greater than 98%).

[0066] Example 4 Preparation of intermediate compound I-4

[0067] Dichloromethane (99 kg) and compound I-3 (2.5 kg) were added to a 180 L reactor. After the addition was complete, the reaction system was cooled to 10 ± 5 °C. At the predetermined temperature, boron tribromide (5.73 kg) was added dropwise to the 180 L reactor. After the addition was complete, the reaction was maintained at 10 ± 5 °C for 5 h. At the end of the reaction, purified water (17.5 kg) was added dropwise to the 180 L reactor. After the addition was complete, the reaction was maintained at 5 ± 5 °C for 2 h. At the predetermined time, the mixture was centrifuged and dried to obtain intermediate compound I-4 (yield > 85%, purity > 99%).

[0068] Example 5 Preparation of Compound I

[0069] Acetonitrile (43.24 kg), compound I-2 (2.19 kg), compound I-4 (2 kg), and potassium carbonate (2.02 kg) were added to a 150 L reactor. The reaction mixture was heated to reflux and maintained at this temperature for 16 h. After the reaction was complete, the mixture was centrifuged. The filter cake and purified water (43.79 kg) were added to a 180 L reactor. The mixture was then kept at 25 ± 5 °C and the reaction was maintained for 2 h. After the predetermined time, the mixture was centrifuged and dried to obtain compound I (yield > 90%, purity > 98%).

[0070] Comparative Example 1: Preparation of intermediate compound I-3 (method reported in patent CN104628686A)

[0071] Step 1, Preparation of Compound II:

[0072] Dichloromethane (6.6 kg) and aluminum trichloride (0.515 kg) were added to a 10 L reactor. After the addition was complete, the reaction system was cooled to 10 ± 5 °C. At the predetermined temperature, oxaloyl chloride (0.490 kg) was added dropwise to the 10 L reactor. After the addition was complete, the temperature was maintained at 10 ± 5 °C for 2 hours. At the predetermined reaction time, a solution of 6-methoxy-2-methylbenzofuran (SM-2, 250 g) / dichloromethane (1.65 kg) was added dropwise to the 10 L reactor. After the addition was complete, the temperature was maintained at 25 ± 5 °C for 8 hours. After the reaction was complete, purified water (2.5 kg) was added to a 20 L reactor. Stirring was started, and under nitrogen protection, the reaction solution was slowly added to the 20 L reactor. After the addition was complete, the mixture was allowed to stand and separated. The resulting organic phase was concentrated to dryness.

[0073] The second step is the preparation of compound I-3:

[0074] The residue obtained in the first step was dissolved in tetrahydrofuran (1.56 kg), and the solution was transferred to a 5 L reactor. After the transfer was complete, methylamine hydrochloride (0.17 kg) and sodium hydroxide solid (70.0 g) were added. After stirring and mixing, the reaction solution was stirred at room temperature for 8 h (the reaction process involved a violent temperature rise and vigorous reflux). After the predetermined reaction time, the reaction solution was concentrated to a residue volume of approximately 1.25 L, and the concentration was completed. Water (3.75 kg) was added at room temperature, and the mixture was stirred at room temperature for 2 h. After centrifugation, intermediate compound I-3 was obtained (yield 80%, purity greater than 97%).

[0075] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing description of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing fruquintinib, characterized in that, Includes the following steps: (1) Add compound SM-1, formamidin or its salt to solvent A, and control the temperature T. A After the reaction was completed, the intermediate compound I-1 was obtained through post-processing. (2) Add compound I-1 and solvent B to thionyl chloride and control the temperature T. B After the reaction was completed, the intermediate compound I-2 was obtained through post-processing. (3) Add oxalyl chloride and aluminum trichloride to solvent Ca, and after the reaction is controlled at temperature, add compound SM-2 and control the temperature T. C1 After reaction ① is completed, compound II is obtained through post-treatment; methylamine or its salt and base C are added to the reaction system in solvent Cb, and the temperature is maintained at T. C2 After reaction ② is completed, intermediate compound I-3 is obtained through post-processing and purification; (4) Add compound I-3 and boron tribromide to solvent D, and control the temperature T. D After the reaction was completed, the intermediate compound I-4 was obtained through post-processing. (5) Add compound I-2, compound I-4, and base E to solvent E, and control the temperature T. E After the reaction was completed, compound I was obtained through post-treatment. The reaction route is as follows: 。 2. The preparation method according to claim 1, characterized in that, In step (1), solvent A is selected from one or more of toluene, N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide; the temperature control T A The temperature is 90–110 °C; the reaction time is 1–10 h; the molar ratio of compound SM-1 to formamidine or its salt is 1:1–2; the formamidine or its salt is one or more of formamidine, formamidine hydrochloride, and formamidine acetate.

3. The preparation method according to claim 1, characterized in that, The solvent B mentioned in step (2) is selected from one or more of N,N-dimethylformamide or N,N-dimethylacetamide; the temperature control T B The temperature is 60–100℃; the reaction time is 2–5 h; and the molar ratio of compound I-1 to thionyl chloride is 1:5–15.

4. The preparation method according to claim 1, characterized in that, The methylamine or its salt mentioned in step (3) is selected from one or more of the following: aqueous methylamine solution, methylamine alcohol solution, methylamine tetrahydrofuran solution, methylamine hydrochloride or methylamine sulfate.

5. The preparation method according to claim 1, characterized in that, The base C mentioned in step (3) is selected from one or more of potassium hydroxide, sodium hydroxide, potassium hydroxide aqueous solution or sodium hydroxide aqueous solution.

6. The preparation method according to claim 1, characterized in that, In step (3), the solvent Ca is selected from one or more of dichloromethane, tetrahydrofuran, or ethyl acetate; the solvent Cb is selected from one or more of dichloromethane, tetrahydrofuran, or ethyl acetate; and the temperature control T... C1 The temperature is 15–35℃; the reaction time ① is 6–9 h; the temperature control T C2 The temperature is 5–20℃; the reaction time is 3–6 h.

7. The preparation method according to claim 1, characterized in that, The molar ratio of compound SM-2 in step (3) to oxalyl chloride, aluminum trichloride, methylamine or its salt, and base C is 1:2.0-3.0:2.0-3.0:8.0-10.0:8.0-10.

0.

8. The preparation method according to claim 1, characterized in that, The solvent D mentioned in step (4) is selected from one or more of dichloromethane, tetrahydrofuran, or ethyl acetate; the temperature control T D The temperature is 5–30°C; the reaction time is 3–6 h; and the molar ratio of compound I-3 to boron tribromide is 1:2–5.

9. The preparation method according to claim 1, characterized in that, The base E mentioned in step (5) is selected from one or more of diisopropylethylamine, potassium carbonate, cesium carbonate, or sodium carbonate.

10. The preparation method according to claim 1, characterized in that, The solvent E mentioned in step (5) is selected from one or more of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, dimethyl sulfoxide, or tetrahydrofuran; the temperature control T E The temperature is 60–70°C; the reaction time is 14–17 h; and the molar ratio of compound I-2 to compound I-4 is 1:1–2.

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