A method for preparing pramipexole
By controlling the temperature of the reaction between trifluoromethylaniline and ethyl 2-cyanoacetoacetate in the presence of an alkaline catalyst and simplifying the post-treatment, the problem of high temperature and high pressure in the preparation of terifluamine was solved, and the synthesis of terifluamine with high yield and high purity was achieved, which is suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHANDONG NEW TIME PHARMA CO LTD
- Filing Date
- 2026-04-23
- Publication Date
- 2026-07-14
AI Technical Summary
Existing methods for preparing teriflumine suffer from problems such as high reaction temperature, low yield, poor stereoselectivity, cumbersome operation, and environmental unfriendliness, making them unsuitable for industrial production.
The reaction of p-trifluoromethylaniline with ethyl 2-cyanoacetoacetate was carried out under controlled temperature in the presence of an alkaline catalyst. Post-treatment included cooling, pH adjustment, filtration and washing with water. High temperature and reduced pressure conditions were avoided. Simple alkaline catalysts such as triethylamine or 4-dimethylaminopyridine were used.
The synthesis of terifluamine with high yield and high purity under mild conditions has been achieved, simplifying the operation, reducing energy consumption and safety risks, and making it suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing teriflunomide. Background Technology
[0002] Teriflunomide, chemically named (Z)-2-cyano-3-hydroxy-N-(4-trifluoromethylphenyl)-2-butenamide, is a leflunomide metabolite developed by Sanofi-Aventis. As a selective dihydroorotate dehydrogenase (DHODH) inhibitor, it is primarily used to treat relapsing-remitting multiple sclerosis (MS). Approved by the U.S. Food and Drug Administration (FDA) in 2012, it has advantages such as oral efficacy, good tolerability, and definite clinical efficacy, making it of significant clinical value. Its structure is as follows: .
[0003] Currently, there are several reported methods for the preparation of teriflunomide in existing technologies. A comprehensive analysis of existing synthetic routes reveals the following main types:
[0004] The first synthetic route: Robert J et al. (J Labelled Compd Radiopharm, 2003, 46:613-622.) reported a five-step reaction involving ethyl acetoacetate, Claisen condensation, cyclization, and hydrolysis to obtain the key intermediate 7, followed by ring-opening under alkaline conditions to yield teriflumine. This method involves multiple reaction steps, low yield, and high cost. The synthetic route is as follows: .
[0005] The second synthetic route: Shi Jingbo et al. (Chinese Pharmaceutical Journal, 2008, 43(17):1353-1354) reacted cyanoacetic acid with phosphorus pentachloride and p-trifluoromethylaniline to prepare intermediate 4. Under sodium hydride conditions, it reacted with acetyl chloride to obtain teriflunomide. The chlorinating reagent used in this route is environmentally harmful, and the use of sodium hydride requires strict operating conditions, resulting in a high risk factor and presenting certain challenges for industrial production. The synthetic route is as follows: .
[0006] Therefore, in view of the problems of high reaction temperature, low yield, poor stereoselectivity, cumbersome operation and environmental unfriendliness in the existing terifluamine preparation methods, there is an urgent need to develop a new green synthesis method for terifluamine with mild reaction conditions, simple operation, high yield, high purity and suitable for industrial scale-up production. Summary of the Invention
[0007] To address the above shortcomings, this invention aims to provide a novel method for preparing teriflumine. This route avoids prolonged reactions under high temperature and reduced pressure conditions, and is simple to operate, offering significant technical advantages.
[0008] This invention is specifically achieved through the following technical solution:
[0009] This invention provides a method for preparing teriflumine, specifically comprising the following steps:
[0010] p-Trifluoromethylaniline and ethyl 2-cyanoacetoacetate were dissolved in an organic solvent, and then an alkaline catalyst was added. The reaction was carried out under controlled temperature. After the reaction was completed, compound I was obtained by post-treatment.
[0011] The synthesis route is as follows: .
[0012] Preferably, the molar ratio of p-trifluoromethylaniline, ethyl 2-cyanoacetoacetate, and alkaline catalyst is 1:1.0~1.8:0.1~0.8; more preferably 1:1.2:0.5.
[0013] Preferably, the organic solvent is selected from any one of toluene, xylene, acetonitrile, and dimethyl sulfoxide; toluene is preferred.
[0014] Preferably, the reaction temperature is 80~140℃, and more preferably 100~120℃.
[0015] Preferably, the alkaline catalyst is selected from sodium hydroxide, sodium carbonate, sodium methoxide, triethylamine, and 4-dimethylaminopyridine, with triethylamine or 4-dimethylaminopyridine being more preferred.
[0016] In a preferred embodiment, post-processing is required after the reaction is completed. The specific steps are as follows: cool to room temperature, add acid, adjust the pH to weakly acidic, solid precipitates, stir, filter, wash with water, and dry.
[0017] Preferably, the acid is selected from dilute hydrochloric acid and dilute sulfuric acid.
[0018] Compared with the prior art, the technical effects achieved by the present invention are as follows:
[0019] 1. Avoids prolonged reactions under high temperature and reduced pressure conditions, ensuring high safety;
[0020] 2. It avoids the use of expensive catalysts, ensuring safety and environmental protection while avoiding the risk of excessive heavy metal content;
[0021] 3. The "one-pot" reaction is mild, and the post-processing purification is simple and easy to operate, with low energy consumption and short processing time. Detailed Implementation
[0022] The present invention will be further illustrated below through embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the invention and not for limiting the invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention are all within the scope of protection of the present invention.
[0023] Preparation of Compound 1
[0024] Example 1
[0025] 161.1 g (1.0 mol) of p-trifluoromethylaniline and ethyl 2-cyanoacetoacetate (186.2 g (1.2 mol) were added to a reaction flask, along with 1600 ml of toluene and 50.0 g (0.5 mol) of triethylamine. The mixture was heated to 100 °C and reacted for 6 h. After cooling to room temperature, dilute hydrochloric acid was added to adjust the pH to weakly acidic. A large amount of solid precipitated out. The mixture was stirred to allow crystals to crystallize, filtered, washed with water, and dried to obtain a white solid with a yield of 97.6% and a purity of 99.87%.
[0026] Example 2
[0027] p-Trifluoromethylaniline (161.1 g, 1.0 mmol) and ethyl 2-cyanoacetoacetate (155.2 g, 1.0 mmol) were added to a reaction flask, along with 1600 ml of acetonitrile and sodium hydroxide (4.0 g, 0.1 mol). The mixture was heated to 80 °C and reacted for 6 h. After cooling to room temperature, dilute hydrochloric acid was added to adjust the pH to weakly acidic. A large amount of solid precipitated out. The mixture was stirred to allow crystals to crystallize, filtered, washed with water, and dried to obtain a white solid with a yield of 94.8% and a purity of 99.66%.
[0028] Example 3
[0029] p-Trifluoromethylaniline (161.1 g, 1.0 mol) and ethyl 2-cyanoacetoacetate (279.3 g, 1.8 mol) were added to a reaction flask, along with 1600 ml of xylene and sodium methoxide (43.2 g, 0.8 mol). The mixture was heated to 140 °C and reacted for 6 h. After cooling to room temperature, dilute hydrochloric acid was added to adjust the pH to weakly acidic. A large amount of solid precipitated out. The mixture was stirred to allow crystals to crystallize, filtered, washed with water, and dried to obtain a white solid with a yield of 95.8% and a purity of 99.72%.
[0030] Example 4
[0031] p-Trifluoromethylaniline (161.1 g, 1.0 mol) and ethyl 2-cyanoacetoacetate (310.3 g, 2.0 mol) were added to a reaction flask, along with 1800 ml of dimethyl sulfoxide and sodium methoxide (54.0 g, 1.0 mol). The mixture was heated to 150 °C and reacted for 6 h. After cooling to room temperature, dilute hydrochloric acid was added to adjust the pH to weakly acidic. A large amount of solid precipitated out. The mixture was stirred to allow crystallization, filtered, washed with water, and dried to obtain a white solid with a yield of 90.6% and a purity of 98.97%.
Claims
1. A method for preparing teriflumine, characterized in that, The preparation method includes the following steps: p-Trifluoromethylaniline and ethyl 2-cyanoacetoacetate were dissolved in an organic solvent, and then an alkaline catalyst was added. The reaction was carried out under controlled temperature. After the reaction was completed, compound I was obtained by post-treatment. The synthesis route is as follows: 。 2. The preparation method according to claim 1, characterized in that, The molar ratio of p-trifluoromethylaniline, ethyl 2-cyanoacetoacetate, and the base catalyst is 1: 1.0~1.8:0.1~0.
8.
3. The preparation method according to claim 1, characterized in that, The organic solvent is selected from any one of toluene, xylene, acetonitrile, and dimethyl sulfoxide.
4. The preparation method according to claim 1, characterized in that, The reaction temperature is 80~140℃.
5. The preparation method according to claim 1, characterized in that, The alkaline catalyst is selected from one of sodium hydroxide, sodium carbonate, sodium methoxide, and triethylamine.