CN-116924937-B - Process for preparing 2-cyano-3-hydroxy-2-butene- (4-trifluoromethyl-phenyl) amide

Abstract

The invention discloses a preparation method of 2-cyano-3-hydroxy-2-butene- (4-trifluoromethyl-phenyl) amide, which comprises the step of reacting a compound shown in a formula (II) with acetyl chloride or acetic anhydride under the action of a base, wherein the base comprises sodium ethoxide and/or sodium methoxide. The sodium alkoxide replaces sodium hydride with higher risk coefficient, reduces the operation difficulty, improves the yield compared with sodium hydride, and is more suitable for industrial production.

Inventors

• XIAO WEI
• WANG LEI
• WANG YOUXIAN
• ZHOU DA
• GU SHASHA
• LI YINGGUANG
• GUO QINGMING

Assignees

• 江苏康缘药业股份有限公司

Dates

Publication Date

20260505

Application Date

20220402

Claims (3)

1. 1. A method for preparing a compound of formula (I) is characterized by comprising the step of reacting a compound of formula (II) with acetyl chloride under the action of alkali, wherein the reaction temperature is-10 ℃ to 5 ℃ and the reaction time is 0.5 to 3 hours, The alkali is sodium methoxide; ; The method further comprises the step of reacting cyanoacetic acid with p-trifluoromethylaniline under the action of a condensing agent, wherein the reaction temperature is 25-55 ℃, the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide, a reaction solvent of a compound of formula (II) and acetyl chloride is tetrahydrofuran, and the molar ratio of the base to the acetyl chloride of formula (II) is 1:3.5:2-1:7.5:6.
2. 2. The method of claim 1, wherein the step of reacting the compound of formula (II) with acetyl chloride comprises: 22mmol of the compound in the formula (II), 50ml of tetrahydrofuran, stirring and dissolving, preserving heat at-5~0 ℃, adding 121mmol of sodium methoxide into the reaction solution, stirring for 30 minutes, controlling the temperature to-5~0 ℃, dropwise adding 88mmol of acetyl chloride into the reaction solution, controlling the temperature to-5 ℃ for reacting for 1-2 hours, adding glacial acetic acid for quenching, adjusting pH to be 7, concentrating under reduced pressure and drying, adding 50ml of water into the concentrate, stirring and pulping for 0.5 hour, filtering, washing with water, adding 50ml of absolute ethyl alcohol into the solid, preserving heat at 40-50 ℃ and stirring for 2 hours, cooling to 0-10 ℃, filtering with suction, and washing with absolute ethyl alcohol.
3. 3. The method according to claim 2, wherein the reaction step of cyanoacetic acid and para-trifluoromethylaniline comprises the steps of adding 62mmol of cyanoacetic acid, 75ml of ethyl acetate and 31mmol of para-trifluoromethylaniline into a reaction bottle, stirring and dissolving, adding 31mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide into the reaction solution at one time, controlling the temperature to be 30-40 ℃ for reaction for 4.5 hours, cooling to room temperature, washing with sodium bicarbonate aqueous solution, washing with hydrochloric acid aqueous solution, washing with sodium chloride aqueous solution, drying with anhydrous sodium sulfate, filtering, concentrating and drying under reduced pressure, adding 20ml of isopropanol into the concentrate, stirring and pulping for 1 hour, filtering, washing with isopropanol, and drying to obtain the compound of the formula (II).

Description

Process for preparing 2-cyano-3-hydroxy-2-butene- (4-trifluoromethyl-phenyl) amide Technical Field The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of (Z) -2-cyano-3-hydroxy-2-butene- (4-trifluoromethyl-phenyl) amide. Background Teriflunomide (Teriflunomide), chemical name (Z) -2-cyano-3-hydroxy-2-butene- (4-trifluoromethyl-phenyl) amide, its structural formula is shown in formula (I): The teriflunomide original grinding medicament is a hydrogen orotate dehydrogenase inhibitor developed by Sainophenanthre, has an immunoregulatory effect, can inhibit experimental allergic encephalomyelitis, is approved in the U.S. for treating adult recurrent type MS in 2012, has the commodity name Aubagio, is approved by EMA for treating adult recurrent-remission type MS in 2013, has the commodity name obacull in 7 in China, and is approved by NMPA for treating Clinical Isolated Syndrome (CIS) in 2020. Disclosure of Invention The invention aims to provide a simple and efficient preparation method of teriflunomide, which has low reaction cost and high yield and is suitable for industrial production. The invention provides a preparation method of a compound of (Z) -2-cyano-3-hydroxy-2-butene- (4-trifluoromethyl-phenyl) amide shown in a formula (I), which comprises the step of reacting a compound of the formula (II) with acetyl chloride or acetic anhydride under the action of alkali, The base comprises sodium ethoxide and/or sodium methoxide, preferably sodium methoxide. Specifically, the reaction solvent includes one or more of tetrahydrofuran, ethyl acetate and methylene chloride, and tetrahydrofuran is preferred. Further, the molar ratio of the formula (II), the base and the acetyl chloride or acetic anhydride is 1:1.5:1-1:9.5:8, preferably 1:3.5:2-1:7.5:6. Further, the reaction temperature is-10 ℃ to 10 ℃, preferably-10 to 5 ℃. Further, the reaction time is 0.5 to 10 hours, preferably 0.5 to 3 hours. Further, the method comprises: 22mmol of the compound of formula (II), 50ml of tetrahydrofuran, were dissolved with stirring. To the reaction solution was added 121mmol of sodium methoxide at-5~0 ℃and stirred for 30 minutes. And (3) dropwise adding 88mmol of acetyl chloride into the reaction solution at the temperature of-5~0 ℃ and the temperature of-5 ℃ for 1-2 hours, adding glacial acetic acid for quenching, adjusting the pH to about 7, concentrating under reduced pressure, adding 50ml of water into the concentrate, stirring and pulping for 0.5 hour, carrying out suction filtration, washing with water, adding 50ml of absolute ethyl alcohol into the solid, carrying out heat preservation and stirring for 2 hours at the temperature of 40-50 ℃, and cooling to 0-10 ℃ for suction filtration and washing with absolute ethyl alcohol. Further, the method of any one of the preceding claims further comprising the step of reacting the cyanoacetic acid with para-trifluoromethylaniline under the influence of a condensing agent. Specifically, the condensing agent is a carbodiimide condensing agent, and may be, for example, 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC). Specifically, the reaction solvent includes one or more of tetrahydrofuran, ethyl acetate, dichloromethane, anhydrous methanol, ethanol, preferably ethyl acetate and/or tetrahydrofuran. Specifically, the molar ratio of the para-trifluoromethylaniline to the cyanoacetic acid to the condensing agent is 0.5:1:1-2:10:5, preferably 0.5:1:1-1:5:3. Further, the reaction temperature is 0 to 80 ℃, preferably 25 to 55 ℃. Specifically, 62mmol of cyanoacetic acid, 75ml of ethyl acetate and 31mmol of para-trifluoromethylaniline are added into a reaction bottle, the mixture is stirred and dissolved, 31mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) is added into the reaction liquid at one time, the temperature is controlled to be 30-40 ℃ for reaction for 4.5 hours, the temperature is reduced to room temperature, the mixture is washed by sodium bicarbonate aqueous solution, hydrochloric acid aqueous solution, sodium chloride aqueous solution and anhydrous sodium sulfate, the mixture is dried by suction filtration and reduced pressure concentration, 20ml of isopropanol is added into the concentrate, stirred and pulped for 1 hour, the mixture is filtered by suction filtration and washed by isopropanol, and the mixture is dried to obtain the compound of the formula (II). The main advantages of the invention are as follows: 1) The invention adopts a one-pot method to react to obtain the compound of the formula (II) and the compound of the formula (I), and EDC/sodium alkoxide is directly added to obtain the product, thereby greatly simplifying experimental operation and being more beneficial to industrial production; 2) According to the invention, sodium alkoxide is used for replacing sodium hydride with a higher risk coefficient, so that the risk of easy ignition of feeding in a high-humidity environment is avoided, alkali i