2-cyano-3-hydroxy-2-buten-(4-trifluoromethyl-phenyl)amide

Abstract

The application discloses a preparation method of 2-cyano-3-hydroxy-2-buten-(4-trifluoromethyl-phenyl)amide, which comprises the following steps: reacting a compound of formula (II) with acetyl chloride or acetic anhydride under the action of a base; wherein the base comprises sodium ethoxide and / or sodium methoxide. In the application, sodium hydride with a relatively high risk coefficient is replaced by sodium alcoholate, the operation difficulty is reduced, the yield is improved compared with sodium hydride, and the application is more suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a method for preparing (Z)-2-cyano-3-hydroxy-2-butene-(4-trifluoromethyl-phenyl)amide. Background Technology

[0002] Teriflunomide, chemically named (Z)-2-cyano-3-hydroxy-2-buten-(4-trifluoromethyl-phenyl)amide, has the structural formula shown in formula (I):

[0003]

[0004] Teriflunomide, developed by Sanofi, is a hydroorotate dehydrogenase inhibitor with immunomodulatory effects. It can inhibit experimental allergic encephalomyelitis. In September 2012, it was approved in the United States for the treatment of relapsed MS in adults under the brand name Aubagio. In September 2013, it was approved by the EMA for the treatment of relapsed-remission MS in adults. In July 2018, it was approved in China for the treatment of relapsed MS under the brand name Aubagio. In 2020, it was approved by the NMPA for the treatment of clinically isolated syndrome (CIS). Summary of the Invention

[0005] The purpose of this invention is to provide a simple and efficient method for preparing teriflumine, which has low reaction cost, high yield, and is suitable for industrial production.

[0006] This invention provides a method for preparing a compound of formula (I) as (Z)-2-cyano-3-hydroxy-2-buten-(4-trifluoromethyl-phenyl)amide, comprising: a step of reacting the compound of formula (II) with acetyl chloride or acetic anhydride under the action of a base; wherein,

[0007] The alkali includes sodium ethoxide and / or sodium methoxide, preferably sodium methoxide.

[0008]

[0009] Specifically, the reaction solvent includes one or more of tetrahydrofuran, ethyl acetate, and dichloromethane, preferably tetrahydrofuran.

[0010] Furthermore, the molar ratio of formula (II), base, and acetyl chloride or acetic anhydride is 1:1.5:1 to 1:9.5:8, preferably 1:3.5:2 to 1:7.5:6.

[0011] Furthermore, the reaction temperature is -10℃ to 10℃, preferably -10℃ to 5℃.

[0012] Furthermore, the reaction time is 0.5 to 10 hours, preferably 0.5 to 3 hours.

[0013] Furthermore, the method includes:

[0014] Dissolve 22 mmol of compound (II) in 50 ml of tetrahydrofuran by stirring. Maintain the temperature at -5 to 0°C, add 121 mmol of sodium methoxide to the reaction mixture, and stir for 30 minutes. Maintain the temperature at -5 to 0°C, add 88 mmol of acetyl chloride dropwise to the reaction mixture, and react at -5 to 5°C for 1 to 2 hours. Quench the reaction with glacial acetic acid, adjust the pH to approximately 7, concentrate under reduced pressure to dryness, add 50 ml of water to the concentrate, stir and slurry for 0.5 hours, filter, wash with water, add 50 ml of anhydrous ethanol to the solid, maintain the temperature at 40 to 50°C and stir for 2 hours, cool to 0 to 10°C, filter, and wash with anhydrous ethanol.

[0015] Furthermore, the method described above also includes the step of reacting cyanoacetic acid with p-trifluoromethylaniline in the presence of a condensing agent.

[0016] Specifically, the condensing agent is a carbodiimide condensing agent, such as 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC).

[0017] Specifically, the reaction solvent includes one or more of tetrahydrofuran, ethyl acetate, dichloromethane, anhydrous methanol, and ethanol, preferably ethyl acetate and / or tetrahydrofuran.

[0018] Specifically, the molar ratio of p-trifluoromethylaniline, cyanoacetic acid and condensing agent is 0.5:1:1 to 2:10:5, preferably 0.5:1:1 to 1:5:3.

[0019] Furthermore, the reaction temperature is 0–80°C, preferably 25–55°C.

[0020] Specifically, 62 mmol of cyanoacetic acid, 75 ml of ethyl acetate, and 31 mmol of p-trifluoromethylaniline were added to the reaction flask and stirred to dissolve. 31 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) was added to the reaction solution in one go. The reaction was carried out at 30-40°C for 4.5 hours. The mixture was then cooled to room temperature, washed with sodium bicarbonate aqueous solution, hydrochloric acid aqueous solution, and sodium chloride aqueous solution, and dried with anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and then added to the concentrate. 20 ml of isopropanol was added and stirred for 1 hour. The mixture was then filtered, washed with isopropanol, and dried to obtain compound (II).

[0021] The main advantages of this invention are as follows:

[0022] 1) In this invention, the reaction is carried out in a one-pot process to obtain compounds of formula (II) and formula (I). By directly adding EDC / sodium alkoxide, the product is obtained well, which greatly simplifies the experimental operation and is more conducive to industrial production.

[0023] 2) This invention uses sodium alkoxide instead of sodium hydride, which has a higher risk factor, thus avoiding the risk of fire when feeding in a humid environment. Moreover, we choose to add the alkali all at once during the feeding process, eliminating the need for dripping. The yield is also higher than that of sodium hydride, making it more suitable for industrial production.

[0024] 3) This invention uses EDC condensing agent, which results in high intermediate purity and good product quality properties. Compared with similar condensing agents such as DIC, DCC, and CDI, the yield is significantly improved.

[0025] 4) Compared with patent WO2017103942A1, the overall yield of compound (Ⅰ) synthesized in this invention is higher;

[0026] 5) 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

[0027] The known methods for preparing teriflumine are synthetic methods, and the main synthetic routes using cyanoacetic acid as the starting material are as follows:

[0028] Patent US6365626B1 discloses that cyanoacetic acid and p-trifluoromethylaniline are reacted with the condensing agent DIC to obtain an intermediate, and the intermediate is then reacted with acetyl chloride in the presence of sodium hydride to obtain teriflumine.

[0029]

[0030] Patent WO2017103942A1 discloses that cyanoacetic acid and p-trifluoromethylaniline are reacted with the condensing agent DCC to obtain an intermediate, and the intermediate is then reacted with acetyl chloride in the presence of sodium hydride to obtain teriflumine.

[0031]

[0032] Both of these methods for preparing teriflumine use highly reactive sodium hydride, which can spontaneously combust in humid air, is highly corrosive, and poses a high risk.

[0033] This invention provides a simple and efficient method for preparing teriflumine, which has low reaction cost, high yield, and is suitable for industrial production.

[0034] This invention uses cyanoacetic acid as a starting material, which reacts with p-trifluoromethylaniline in the presence of a condensing agent to obtain formula (II). Formula (II) then reacts with acetyl chloride or acetic anhydride in the presence of a base to obtain formula (I). The reaction route is as follows:

[0035]

[0036] The following will provide a detailed description based on the experimental examples.

[0037] 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.

[0038] 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.

[0039] Process condition screening

[0040] Screening of process conditions for synthetic (II) compound condensing agents

[0041] Add 5.28 g (62 mmol) of cyanoacetic acid, 75 ml of ethyl acetate, and 5 g (31 mmol) of p-trifluoromethylaniline to a reaction flask, stir to dissolve, and then add 31 mmol of the corresponding condensing agent to the reaction solution all at once. React at 30–40 °C for 4.5 hours. Cool to room temperature, wash with sodium bicarbonate aqueous solution, hydrochloric acid aqueous solution, and sodium chloride aqueous solution, and dry with anhydrous sodium sulfate; filter under vacuum and concentrate to dryness under reduced pressure. Add 20 ml of isopropanol to the concentrate and stir for 1 hour, filter, wash with isopropanol, and dry to obtain compound (II).

[0042] Comparison Table of Synthetic (II) Compound Condensing Agents

[0043] Types of condensing agents reaction solvent reaction time reaction temperature Material proportions yield EDC EA 4.5h 30～40℃ 1:2 86.4％ DCC EA 4.5h 30～40℃ 1:2 60.2％ DIC EA 4.5h 30～40℃ 1:2 64.8％ CDI EA 4.5h 30～40℃ 1:2 57.5％ HOBT EA 4.5h 30～40℃ 1:2 No precipitation

[0044] Material ratio = p-trifluoromethylaniline : cyanoacetic acid

[0045] Conclusion: Under the same reaction conditions, no compound of formula (II) was precipitated when using the condensing agent HOBT (1-hydroxybenzotriazole). Compound of formula (II) could be obtained when using the condensing agents DCC (N,N'-dicyclohexylcarbodiimide), DIC (N,N'-diisopropylcarbodiimide), and CDI (N,N'-carbonyldiimidazole), but the yield was more than 20% lower than that when using EDC (1-ethyl-(3-dimethylaminopropyl)carbodiimide).

[0046] Screening of process conditions for the types of bases in synthetic formula (I) compounds

[0047] Add 5 g (22 mmol) of 2-cyano-N-(4-trifluoromethylaniline)-amide and 50 ml of tetrahydrofuran to the reaction flask and stir to dissolve. Maintain the temperature at -5 to 0°C, add 121 mmol of the corresponding base to the reaction solution, and stir for 30 minutes. Maintain the temperature at -5 to 0°C, add 6.8 g (88 mmol) of acetyl chloride dropwise to the reaction solution, and react at -5 to 5°C for 1 to 2 hours. Quench with glacial acetic acid, adjust the pH to approximately 7, concentrate under reduced pressure to dryness, add 50 ml of water to the concentrate and stir for 0.5 hours, filter, wash with water, add 50 ml of anhydrous ethanol to the solid, maintain the temperature at 40 to 50°C and stir for 2 hours, cool to 0 to 10°C, filter, and wash with anhydrous ethanol. Dry to obtain compound (Ⅰ).

[0048] Comparison table of base types for synthetic formula (I) compounds

[0049] Types of alkalis reaction solvent reaction time reaction temperature Material proportions yield NaOH THF 2h -5～0℃ 1:5.5:4 Oily substance precipitated NaCO3 THF 2h -5～0℃ 1:5.5:4 No response Sodium methoxide THF 2h -5～0℃ 1:5.5:4 83.3％ Sodium ethoxide THF 2h -5～0℃ 1:5.5:4 73.8％ NaH THF 2h -5～0℃ 1:5.5:4 80.2％

[0050] Material ratio = 2-cyano-N-(4-trifluoromethylaniline)-amide : sodium methoxide : acetyl chloride

[0051] Conclusion: Sodium alkoxide has a higher safety factor, and the product yield obtained by sodium methoxide is even higher than that of sodium hydride. Therefore, the use of sodium alkoxide not only avoids the risk of fire when feeding in a high humidity environment, but also allows for the one-time addition of alkali during the feeding process, eliminating the need for dripping, which is more conducive to industrial production. Detailed Implementation

[0053] Example 1: Preparation of 2-cyano-N-(4-trifluoromethylaniline)-amide

[0054] Add 5.28 g of cyanoacetic acid, 75 ml of ethyl acetate, and 5 g of p-trifluoromethylaniline to a reaction flask, stir to dissolve, and then add 4.82 g of EDC solution to the reaction solution in one go. React at 30–40 °C for 4.5 hours. Cool to room temperature, wash with sodium bicarbonate aqueous solution, hydrochloric acid aqueous solution, and sodium chloride aqueous solution, and dry with anhydrous sodium sulfate; filter under vacuum and concentrate to dryness under reduced pressure. Add 20 ml of isopropanol to the concentrate and stir for 1 hour, filter, wash with isopropanol, and dry to obtain 6.12 g of white solid, yield: 86.4%.

[0055] Example 2: Preparation of (Z)-2-cyano-3-hydroxy-2-butene-(4-trifluoromethyl-phenyl)amide

[0056] Add 5g of 2-cyano-N-(4-trifluoromethylaniline)-amide and 50ml of tetrahydrofuran to a reaction flask and stir to dissolve. Maintain the temperature at -5 to 0℃, then add 6.5g of sodium methoxide solid to the reaction solution and stir for 30 minutes. Maintain the temperature at -5 to 0℃, then add 6.8g of acetyl chloride dropwise to the reaction solution and react at -5 to 5℃ for 1 to 2 hours. Quench with glacial acetic acid, adjust the pH to approximately 7, concentrate under reduced pressure to dryness, add 50ml of water to the concentrate and stir for 0.5 hours, filter, wash with water, add 50ml of anhydrous ethanol to the solid, maintain the temperature at 40 to 50℃ and stir for 2 hours, cool to 0 to 10℃, filter, and wash with anhydrous ethanol. Dry to obtain 4.92g of white solid, yield: 83.3%.

[0057] Example 3: Preparation of 2-cyano-N-(4-trifluoromethylaniline)-amide

[0058] Add 21.12 g of cyanoacetic acid, 300 ml of ethyl acetate, and 20 g of p-trifluoromethylaniline to a reaction flask, stir to dissolve, and then add 19.28 g of EDC solution to the reaction solution in one go. React at 40–50 °C for 5 hours. Cool to room temperature, wash with sodium bicarbonate aqueous solution, hydrochloric acid aqueous solution, and sodium chloride aqueous solution, and dry with anhydrous sodium sulfate; filter under vacuum and concentrate to dryness under reduced pressure. Add 80 ml of isopropanol to the concentrate, stir at -5–5 °C for 1 hour, filter under vacuum, wash with isopropanol, and dry to obtain 26.1 g of white solid, yield: 92.4%.

[0059] Example 4: Preparation of (Z)-2-cyano-3-hydroxy-2-buten-(4-trifluoromethyl-phenyl)amide

[0060] Add 25g of 2-cyano-N-(4-trifluoromethylaniline)-amide and 250ml of tetrahydrofuran to a reaction flask and stir to dissolve. Maintain the temperature at -5 to 0℃, then add 32.5g of sodium methoxide solid to the reaction solution and stir for 30 minutes. Maintain the temperature at -5 to 0℃, then add 34.4g of acetyl chloride dropwise to the reaction solution and react at -5 to 5℃ for 1 to 2 hours. Quench with glacial acetic acid, adjust the pH to approximately 7, concentrate under reduced pressure to dryness, add 50ml of water to the concentrate and stir for 0.5 hours, filter, wash with water, add 250ml of anhydrous ethanol to the solid, maintain the temperature at 40 to 50℃ and stir for 2 hours, cool to 0 to 10℃, filter, and wash with anhydrous ethanol. Dry to obtain 26.2g of white solid, yield: 88.5%.

[0061] Example 5: Preparation of 2-cyano-N-(4-trifluoromethylaniline)-amide

[0062] Add 7.92 g of cyanoacetic acid, 75 ml of tetrahydrofuran, and 5 g of p-trifluoromethylaniline to a reaction flask, stir to dissolve, and then add 4.82 g of EDC solution to the reaction solution all at once. React at 40–50 °C for 6 hours. Cool to room temperature, wash with sodium bicarbonate aqueous solution, hydrochloric acid aqueous solution, and sodium chloride aqueous solution, and dry to anhydrous sodium sulfate; filter under vacuum and concentrate to dryness under reduced pressure. Add 20 ml of isopropanol to the concentrate and stir for 1 hour, filter, wash with isopropanol, and dry to obtain 6.04 g of white solid, yield: 91.3%.

[0063] Example 6: Preparation of (Z)-2-cyano-3-hydroxy-2-butene-(4-trifluoromethyl-phenyl)amide

[0064] Add 5g of 2-cyano-N-(4-trifluoromethylaniline)-amide and 50ml of ethyl acetate to a reaction flask and stir to dissolve. Maintain the temperature at -5 to 0℃, then add 6.5g of sodium methoxide solid to the reaction solution and stir for 30 minutes. Maintain the temperature at -5 to 0℃, then add 6.8g of acetyl chloride dropwise to the reaction solution and react at -5 to 5℃ for 1 hour. Quench with glacial acetic acid, adjust the pH to approximately 7, concentrate under reduced pressure to dryness, add 50ml of water to the concentrate and stir for 0.5 hours, filter, wash with water, add 50ml of anhydrous ethanol to the solid, maintain the temperature at 40 to 50℃ and stir for 2 hours, cool to 0 to 10℃, filter, and wash with anhydrous ethanol. Dry to obtain 4.83g of white solid, yield: 85.6%.

[0065] Example 7: Preparation of 2-cyano-N-(4-trifluoromethylaniline)-amide

[0066] Add 5.28 g of cyanoacetic acid, 75 ml of anhydrous ethanol, and 5 g of p-trifluoromethylaniline to a reaction flask, stir to dissolve, and then add 4.82 g of EDC solution to the reaction solution in one go. React at 10–20 °C for 6 hours. Cool to room temperature, wash with sodium bicarbonate aqueous solution, hydrochloric acid aqueous solution, and sodium chloride aqueous solution, and dry with anhydrous sodium sulfate; filter under vacuum and concentrate to dryness under reduced pressure. Add 20 ml of isopropanol to the concentrate, stir and slurry for 1 hour, filter, wash with isopropanol, and dry to obtain 5.21 g of white solid, yield: 89.6%.

[0067] Example 8: Preparation of (Z)-2-cyano-3-hydroxy-2-butene-(4-trifluoromethyl-phenyl)amide

[0068] Add 5g of 2-cyano-N-(4-trifluoromethylaniline)-amide and 50ml of dichloromethane to a reaction flask and stir to dissolve. Maintain the temperature at -10 to -5℃, then add 6.5g of sodium methoxide solid to the reaction solution and stir for 30 minutes. Maintain the temperature at -5 to 0℃, then add 6.8g of acetyl chloride dropwise to the reaction solution and react at -5 to 5℃ for 5 hours. Quench with glacial acetic acid, adjust the pH to approximately 7, concentrate under reduced pressure to dryness, add 50ml of water to the concentrate and stir for 0.5 hours, filter, wash with water, add 50ml of anhydrous ethanol to the solid, maintain the temperature at 40-50℃ and stir for 2 hours, cool to 0-10℃, filter, and wash with anhydrous ethanol. Dry to obtain 4.21g of white solid, yield: 87.1%.

[0069] Example 9: Preparation of 2-cyano-N-(4-trifluoromethylaniline)-amide

[0070] Add 10.56 g of cyanoacetic acid, 75 ml of dichloromethane, and 5 g of p-trifluoromethylaniline to a reaction flask, stir to dissolve, and then add 4.82 g of EDC solution to the reaction solution all at once. React at 10–20 °C for 6 hours. Cool to room temperature, wash with sodium bicarbonate aqueous solution, hydrochloric acid aqueous solution, and sodium chloride aqueous solution, and dry with anhydrous sodium sulfate; filter under vacuum and concentrate to dryness under reduced pressure. Add 20 ml of isopropanol to the concentrate and stir for 1 hour, filter, wash with isopropanol, and dry to obtain 4.93 g of white solid, yield: 90.7%.

[0071] Example 10: Preparation of (Z)-2-cyano-3-hydroxy-2-butene-(4-trifluoromethyl-phenyl)amide

[0072] Add 5g of 2-cyano-N-(4-trifluoromethylaniline)-amide and 50ml of tetrahydrofuran to a reaction flask and stir to dissolve. Maintain the temperature at 10–20°C, then add 6.5g of sodium methoxide solid to the reaction solution and stir for 30 minutes. Control the temperature at -5–0°C, then add 6.8g of acetyl chloride dropwise to the reaction solution and react at -5–5°C for 10 hours. Quench with glacial acetic acid, adjust the pH to approximately 7, concentrate under reduced pressure to dryness, add 50ml of water to the concentrate and stir for 0.5 hours, filter, wash with water, add 50ml of anhydrous ethanol to the solid, maintain the temperature at 40–50°C and stir for 2 hours, cool to 0–10°C, filter, and wash with anhydrous ethanol. Dry to obtain 3.98g of white solid, yield: 86.2%.

[0073] 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: The reaction of compound (II) with acetyl chloride under alkaline conditions occurs at a temperature of -10℃ to 5℃ for 0.5 to 3 hours; wherein, The alkali is sodium methoxide; ； The method further includes a step of reacting cyanoacetic acid with p-trifluoromethylaniline under the action of a condensing agent at a reaction temperature of 25–55°C, wherein the condensing agent is 1-ethyl-(3-dimethylaminopropyl)carbodiimide; wherein the reaction solvent for the compound of formula (II) with acetyl chloride is tetrahydrofuran; and the molar ratio of formula (II), base and acetyl chloride is 1:3.5:2 to 1:7.5:

6.

2. The method according to claim 1, characterized in that, The reaction steps of compound (II) with acetyl chloride include: 22 mmol of compound (II) was dissolved in 50 ml of tetrahydrofuran by stirring and kept at -5 to 0 °C. 121 mmol of sodium methoxide was added to the reaction solution and stirred for 30 minutes. The temperature was kept at -5 to 0 °C. 88 mmol of acetyl chloride was added dropwise to the reaction solution and the temperature was kept at -5 to 5 °C for 1 to 2 hours. Glacial acetic acid was added to quench the reaction and the pH was adjusted to 7. The solution was concentrated to dryness under reduced pressure. 50 ml of water was added to the concentrate and stirred for 0.5 hours. The solution was filtered and washed with water. 50 ml of anhydrous ethanol was added to the solid and stirred at 40 to 50 °C for 2 hours. The solution was cooled to 0 to 10 °C and filtered and washed with anhydrous ethanol.

3. The method according to claim 2, characterized in that, The reaction steps of cyanoacetic acid and p-trifluoromethylaniline include: adding 62 mmol of cyanoacetic acid, 75 ml of ethyl acetate, and 31 mmol of p-trifluoromethylaniline to a reaction flask, stirring to dissolve, adding 31 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide to the reaction solution at once, reacting at 30-40℃ for 4.5 hours, cooling to room temperature, washing with sodium bicarbonate aqueous solution, hydrochloric acid aqueous solution, sodium chloride aqueous solution, and drying with anhydrous sodium sulfate; filtering, concentrating under reduced pressure to dryness, adding 20 ml of isopropanol to the concentrate, stirring and slurrying for 1 hour, filtering, washing with isopropanol, and drying to obtain compound (II).

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