A method for preparing teriflunomide

Abstract

This invention discloses a method for preparing teriflumine, comprising the step of reacting p-trifluoromethylaniline with 5-methylisoxazole-4-carboxylic acid in the presence of a catalyst; wherein the catalyst comprises one or more of EDC and CDI. This invention employs a one-pot reaction to directly obtain the teriflumine product, resulting in a significantly improved yield compared to existing methods. The raw materials and reagents used are inexpensive and readily available, the reaction conditions are mild, the operation is simple, and it is environmentally friendly, making it suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a novel method for preparing teriflunomide. Background Technology

[0002] Teriflunomide, traded as Aubagio, has the chemical name (Z)-2-cyano-3-hydroxy-2-buten-(4-trifluoromethyl-phenyl)amide, and its structural formula is shown in formula (I).

[0003]

[0004] Teriflunomide, originally developed by Sanofi, is indicated for the treatment of relapsing-remitting multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS. It was approved in the United States in September 2012 for the treatment of adult relapsing MS, by the EMA in September 2013 for the treatment of adult relapsing-remitting MS, approved in China in July 2018 for the treatment of relapsing MS, and by the NMPA in 2020 for the treatment of clinically isolated syndrome (CIS).

[0005] Teriflunomide is effective in treating MS, not only significantly reducing the annual relapse rate of MS, but also reducing the risk of disability progression. Summary of the Invention

[0006] The purpose of this invention is to provide a simple and efficient method for preparing terifluamine, which has low reaction cost, high yield, and is suitable for industrial production.

[0007] This invention provides a method for preparing a compound of formula (I), comprising: reacting p-trifluoromethylaniline with 5-methylisoxazole-4-carboxylic acid in the presence of a catalyst; wherein,

[0008]

[0009] The catalysts include EDC (1-ethyl-(3-dimethylaminopropyl)carbodiimide) and CDI (N,N'-carbonyldiimidazole), with EDC being preferred.

[0010] Specifically, the solvent for the reaction includes one or more of tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, DMF, and 1,4-dioxane, preferably dichloromethane and acetonitrile.

[0011] Specifically, the molar ratio of p-trifluoromethylaniline:catalyst:5-methylisoxazole-4-carboxylic acid is 1:1:1 to 1:10:12, preferably 1:1:1 to 1:5:6.

[0012] Specifically, the reaction temperature is 5℃~120℃, preferably 30~70℃.

[0013] Specifically, the reaction time is 2 to 24 hours, preferably 4 to 10 hours.

[0014] Furthermore, the method also includes the step of adding acid to precipitate the product after the reaction is completed.

[0015] Specifically, the acid includes one or more of hydrochloric acid, sulfuric acid, formic acid, and acetic acid, with hydrochloric acid being preferred.

[0016] Specifically, the method for preparing compound (I) provided by the present invention includes:

[0017] Add p-trifluoromethylaniline, 5-methylisoxazole-4-carboxylic acid and catalyst to the reaction solvent, stir to dissolve, and react. After the reaction is completed, cool down and control the temperature at -5 to 5℃. Add acid to the reaction solution to precipitate solid, stir, filter, wash with water and anhydrous ethanol, and dry.

[0018] Specifically, the method of the present invention includes:

[0019] Add 5g of p-trifluoromethylaniline, 5.92g of 5-methylisoxazole-4-carboxylic acid, and 9.63g of EDC to 100ml of dichloromethane reaction solvent, stir to dissolve, react at 30-35℃, detect the end of the reaction, cool down, control the temperature at -5-5℃, add dilute hydrochloric acid to the reaction solution, precipitate solid, keep warm and stir, filter, wash with water and anhydrous ethanol, and dry.

[0020] The main advantages of this invention are as follows:

[0021] 1) This invention uses a one-pot reaction to directly obtain terifluamine. The starting materials and catalyst are directly added to the reaction solution, and after the reaction is complete, acid is added to precipitate the solid. After filtration, the product is obtained. This invention creatively provides a new synthetic method for the preparation of terifluamine.

[0022] 2) The catalysts EDC (1-ethyl-(3-dimethylaminopropyl)carbodiimide) and CDI (N,N'-carbonyldiimidazole) used in this invention act as both condensing agents and base ring-opening agents in the reaction, allowing teriflumine to be obtained directly in a one-pot process.

[0023] 3) Compared with existing preparation methods, the teriflumine preparation method of the present invention not only shortens the reaction operation steps and does not use special reagents, but also greatly improves the yield of teriflumine and produces a white solid with good product quality.

[0024] 4) The raw materials and reagents used in this invention are inexpensive and readily available, the reaction conditions are mild, the operation is simple, and it is environmentally friendly and suitable for large-scale production. Detailed Implementation

[0025] The known methods for preparing teriflumine are synthetic methods, and the main synthetic routes using 5-methylisoxazole-4-carboxylic acid as the starting material are as follows:

[0026] Patents WO2015029063A2 and CN201010509576.2 disclose that 5-methylisoxazole-4-carboxylic acid is first chlorinated in the presence of a chlorinating agent and then reacted with p-trifluoromethylaniline to obtain leflunomide intermediate, and leflunomide is hydrolyzed to obtain teriflunomide.

[0027]

[0028] This method involves a lengthy process, and the chlorinating reagents used, such as thionyl chloride, triphosgene, and diphosgene, are toxic and highly corrosive. In industrial production, they are highly corrosive to production equipment, and the wastewater and waste gas generated after the reaction are harmful to the environment. Furthermore, the overall yield is relatively low.

[0029] Patents CN200910025144.1, CN202010254354.4, and CN202110351523.0 disclose that 5-methylisoxazole-4-carboxylic acid reacts directly with p-trifluoromethylaniline in the presence of a condensing agent to obtain leflunomide intermediate, and leflunomide is hydrolyzed to obtain teriflunomide.

[0030]

[0031] This method involves a lengthy process, requiring the activation of 5-methylisoxazole-4-carboxylic acid and a condensing agent under alkaline conditions, followed by reaction with p-trifluoromethylaniline to obtain leflunomide intermediate. Leflunomide is then hydrolyzed to yield teriflunomide, resulting in a low yield of the teriflunomide product.

[0032] This invention provides a simple and efficient method for preparing teriflumine, which has low reaction cost, high yield, and is suitable for industrial production.

[0033] This invention uses p-trifluoromethylaniline as a starting material, reacting it with 5-methylisoxazole-4-carboxylic acid in the presence of a catalyst to directly obtain formula (Ⅰ). The reaction route is as follows:

[0034]

[0035] The following will provide a detailed description based on the experimental examples.

[0036] It is particularly important to note that similar substitutions and modifications made to this invention are obvious to those skilled in the art, and they are all considered to be included in this invention. Those skilled in the art will clearly be able to modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to implement and apply the technology of this invention. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments.

[0037] Unless otherwise specified, this invention is carried out under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0038] Process condition screening

[0039] Screening of Synthetic (I) Compounding Process Conditions

[0040] Add p-trifluoromethylaniline, 5-methylisoxazole-4-carboxylic acid, and catalyst to the reaction solvent, stir to dissolve, and react under controlled temperature. Once the reaction is complete, lower the temperature and control it between -5 and 5°C. Add acid to the reaction solution, and a large amount of solid precipitates. Keep the mixture warm and stir. Filter, wash with water and anhydrous ethanol, and dry to obtain compound (Ⅰ).

[0041] Comparison Table of Synthetic Processes for Compounds of Form I

[0042]

[0043]

[0044] Material ratio = p-Trifluoromethylaniline : Catalyst : 5-Methylisoxazole-4-carboxylic acid

[0045] Conclusion: Under the same reaction conditions, the catalysts HOBT (1-hydroxybenzotriazole), DCC (N,N'-dicyclohexylcarbodiimide), DIC (N,N'-diisopropylcarbodiimide), and EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) failed to yield compound (I). The catalysts CDI (N,N'-carbonyldiimidazole) and EDC (1-ethyl-(3-dimethylaminopropyl)carbodiimide) both yielded compound (I), but the other catalysts could not simultaneously perform ring-opening and condensation, thus failing to produce teriflumine products. Both EDC and CDI catalysts yielded teriflumine products, with EDC producing a higher yield. Detailed Implementation

[0047] Example 1: Preparation of teriflunomide

[0048] Add 5 g (31 mmol) of p-trifluoromethylaniline, 5.92 g (46.5 mmol) of 5-methylisoxazol-4-carboxylic acid, and 9.63 g (62 mmol) of EDC to 100 ml of dichloromethane reaction solvent. Stir to dissolve and react at 30–35 °C for 4–5 hours. After the reaction is complete, cool the mixture and control the temperature at -5–5 °C. Add dilute hydrochloric acid to the reaction solution, and a large amount of solid precipitates. Keep the mixture warm and stir. Filter, wash with water and anhydrous ethanol, and dry to obtain 7.63 g of white solid, yield 91%.

[0049] Example 2: Preparation of teriflunomide

[0050] Add 5 g (31 mmol) of p-trifluoromethylaniline, 5.92 g (46.5 mmol) of 5-methylisoxazol-4-carboxylic acid, and 10.06 g (62 mmol) of CDI to 100 ml of dichloromethane reaction solvent. Stir to dissolve and react at 30–35 °C for 4–5 hours. After the reaction is complete, cool the mixture and control the temperature at -5–5 °C. Add dilute hydrochloric acid to the reaction solution, and a large amount of solid precipitates. Keep the mixture warm and stir. Filter, wash with water and anhydrous ethanol, and dry to obtain 6.28 g of compound (I), yield 75%.

[0051] Example 3: Preparation of teriflunomide

[0052] Add 5 g (31 mmol) of p-trifluoromethylaniline, 5.92 g (46.5 mmol) of 5-methylisoxazol-4-carboxylic acid, and 9.63 g (62 mmol) of EDC to 100 ml of ethyl acetate reaction solvent. Stir to dissolve and react at 25–30 °C for 4–5 hours. After the reaction is complete, cool the mixture and control the temperature at -5–5 °C. Add dilute sulfuric acid to the reaction solution, and a large amount of solid precipitates. Keep the mixture warm and stir. Filter, wash with water and anhydrous ethanol, and dry to give 7.37 g of white solid, yield 88%.

[0053] Example 4: Preparation of teriflumine

[0054] Add 5 g (31 mmol) of p-trifluoromethylaniline, 5.92 g (46.5 mmol) of 5-methylisoxazol-4-carboxylic acid, and 9.63 g (62 mmol) of EDC to 100 ml of acetonitrile reaction solvent. Stir to dissolve and react at 40–50 °C for 4–5 hours. After the reaction is complete, cool the mixture and control the temperature at -5–5 °C. Add acetic acid to the reaction solution, and a large amount of solid precipitates. Keep the mixture warm and stir. Filter, wash with water and anhydrous ethanol, and dry to obtain 7.45 g of white solid, yield 89%.

[0055] Example 5: Preparation of teriflumine

[0056] Add 5 g (31 mmol) of p-trifluoromethylaniline, 5.92 g (46.5 mmol) of 5-methylisoxazol-4-carboxylic acid, and 19.26 g (124 mmol) of EDC to 100 ml of dichloromethane reaction solvent. Stir to dissolve and react at 25–30 °C for 4–5 hours. After the reaction is complete, cool the mixture and control the temperature at -5–5 °C. Add dilute hydrochloric acid to the reaction solution, and a large amount of solid precipitates. Keep the mixture warm and stir. Filter, wash with water and anhydrous ethanol, and dry to obtain 7.5 g of white solid, yield 89.5%.

[0057] Example 6: Preparation of teriflumine

[0058] Add 5 g (31 mmol) of p-trifluoromethylaniline, 5.92 g (46.5 mmol) of 5-methylisoxazol-4-carboxylic acid, and 20.12 g (124 mmol) of CDI to 100 ml of ethyl acetate reaction solvent. Stir to dissolve and react at 40–55 °C for 4–5 hours. After the reaction is complete, cool the mixture and control the temperature at -5–5 °C. Add dilute sulfuric acid to the reaction solution, and a large amount of solid precipitates. Keep the mixture warm and stir. Filter, wash with water and anhydrous ethanol, and dry to obtain 6.03 g of compound (I), yield 72%.

[0059] Example 7: Preparation of teriflumine

[0060] Add 5 g (31 mmol) of p-trifluoromethylaniline, 5.92 g (46.5 mmol) of 5-methylisoxazol-4-carboxylic acid, and 10.06 g (62 mmol) of CDI to 100 ml of acetonitrile reaction solvent. Stir to dissolve and react at 30–35 °C for 4–5 hours. After the reaction is complete, cool the mixture and control the temperature at -5–5 °C. Add acetic acid to the reaction solution, and a large amount of solid precipitates. Keep the mixture warm and stir. Filter, wash with water and anhydrous ethanol, and dry to obtain 5.45 g of compound (I), yield 65%.

[0061] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a compound of formula (I), characterized in that, include: p-Trifluoromethylaniline, 5-methylisoxazole-4-carboxylic acid, and a catalyst were added to the reaction solvent, stirred to dissolve, and reacted. After the reaction was completed, the temperature was lowered and controlled at -5 to 5°C. Acid was added to the reaction solution, and a solid precipitated. The mixture was stirred, filtered, washed with water and anhydrous ethanol, and dried. The catalyst was EDC. The solvent for the reaction is selected from one or more of ethyl acetate, dichloromethane, and acetonitrile.

2. The method according to claim 1, characterized in that, The molar ratio of p-trifluoromethylaniline, catalyst, and 5-methylisoxazole-4-carboxylic acid is 1:1:1 to 1:5:

6.

3. The method according to claim 1, characterized in that, The reaction temperature is 30–70℃.

4. The method according to claim 1, characterized in that, The reaction time is 4 to 10 hours.

5. The method according to claim 1, characterized in that, The acid includes one or more of hydrochloric acid, sulfuric acid, and acetic acid.

6. The method according to claim 1, characterized in that, include: Add 5g of p-trifluoromethylaniline, 5.92g of 5-methylisoxazole-4-carboxylic acid, and 9.63g of EDC to 100ml of dichloromethane, stir to dissolve, react at 30-35℃, detect the end of the reaction, cool down, control the temperature at -5-5℃, add dilute hydrochloric acid to the reaction solution, precipitate solid, keep warm and stir, filter, wash with water and anhydrous ethanol, and dry.

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