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Simple preparation method of teriflunomide

A kind of teriflunomide, simple technology, applied in the field of preparation of teriflunomide, can solve the problem of low yield of end product teriflunomide and the like

Inactive Publication Date: 2021-07-06
THE THIRD AFFILIATED HOSPITAL OF SUN YAT SEN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] Although the third synthetic method does not use an acylating reagent and the intermediate product does not need to be purified, the yield of the final product teriflunomide is low

Method used

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  • Simple preparation method of teriflunomide
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  • Simple preparation method of teriflunomide

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preparation example Construction

[0042] The invention provides a kind of simple and convenient preparation method of teriflunomide, comprises the following steps:

[0043] (1) condensing 5-methylisoxazole-4-carboxylic acid and a condensing agent in a solvent under alkaline conditions to obtain an active ester system;

[0044] (2) Condensing the active ester system and 4-trifluoromethylaniline in a solvent to obtain the intermediate leflunomide;

[0045] (3) The obtained intermediate leflunomide is subjected to alkali treatment and acid treatment in sequence to obtain teriflunomide.

[0046] In step (1) of the present invention, the solvent is acetone, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, toluene, benzene, xylene, N,N-dimethylformamide, di One or more of methyl sulfoxide, diethyl ether, tetrahydrofuran and dioxane, preferably dichloromethane or N,N-dimethylformamide.

[0047] In step (1) of the present invention, the condensing agent is carbonyl imidazole, benzotria...

Embodiment 1

[0064] (1) Preparation of active ester

[0065] 50g (0.39mol) of 5-methylisoxazole-4-carboxylic acid was dissolved in 500ml of dichloromethane and placed in an ice bath; 245g of 2-(7-azabenzotriazole)-N,N,N' , N'-tetramethyluronium hexafluorophosphate (0.65mol) was added to the above reaction system and 100.81g (0.78mol) N,N-diisopropylethylamine was added, and the active ester was obtained after stirring in an ice bath for 1 hour , this step does not require purification and post-treatment, and is directly used in the next reaction.

[0066] (2) Preparation of intermediate leflunomide

[0067] Add 100 g (0.62 mol) of 4-trifluoromethylaniline into the above-mentioned active ester reaction system, stir at 0°C for 3 h, and track the reaction by TLC until the reaction of the raw materials is complete. After the reaction, the reaction solution was poured into 1 L of ice water and stirred for 30 min, a large amount of white solid was precipitated, filtered, the filter cake was wa...

Embodiment 2

[0073] (1) Preparation of active ester

[0074] 50g (0.39mol) of 5-methylisoxazole-4-carboxylic acid was dissolved in 500ml of methylene chloride and placed in an ice bath; 368.4g (0.65mol) of hexafluorophosphate benzotriazol-1-yl-oxyl Tripyrrolidinylphosphine was added to the above reaction system and 78.93g (0.78mol) of triethylamine was added. After stirring in an ice bath for 1 hour, the active ester was obtained. This step did not require purification and post-treatment, and was directly used in the next reaction.

[0075] (2) The preparation of intermediate leflunomide is the same as in Example 1

[0076] (3) Preparation of Teriflunomide

[0077] Suspend 50 g (0.19 mol) of the intermediate leflunomide in 500 mL of water, add 74.07 g (1.32 mol) of potassium hydroxide to react until clarified, then react at room temperature for 2 h, and track the reaction to completion by TLC. After the reaction, 1N hydrochloric acid was added dropwise to the reaction solution to adjust ...

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Abstract

The invention provides a simple preparation method of teriflunomide, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps of: (1) mixing 5-methylisoxazole-4-formic acid and a condensing agent in a solvent under an alkaline condition, and carrying out condensation reaction to obtain an active ester system; (2) mixing the active ester system and 4-trifluoromethylaniline in a solvent, and carrying out condensation reaction to obtain an intermediate leflunomide; and (3) carrying out alkali treatment and acid treatment on the obtained intermediate leflunomide to obtain teriflunomide. According to the method, the 5-methylisoxazole-4-formic acid reacts with the 4-trifluoromethylaniline in the form of active ester, so that the reaction activity of the 5-methylisoxazole-4-formic acid and the 4-trifluoromethylaniline is improved, the reaction condition is mild, the obtained intermediate leflunomide does not need to be purified, and the yield of teriflunomide is improved.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a simple and convenient preparation method of teriflunomide. Background technique [0002] Teriflunomide, chemical name: (2Z)-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide. Teriflunomide is a dihydroorotate dehydrogenase (DHODH) inhibitor and an active metabolite of leflunomide (Leflunomide). Teriflunomide is a new drug for the treatment of multiple sclerosis (MS) successfully developed by Sanofi-Aventis. It was approved by the FDA in September 2012 and is suitable for the treatment of relapsing MS in adults. multiple sclerosis. In-depth research on teriflunomide is also carried out in China today, but it is mainly used for the treatment of skin diseases. The molecular formula of teriflunomide is: C 12 h 9 f 3 N 2 o 2 , the molecular weight is 270.06, and the structure is shown in Formula 1. [0003] [0004] At present, the preparation method...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/23C07C253/00
CPCC07C253/00C07D261/18
Inventor 邱伟陈晨汤有志张光雨
Owner THE THIRD AFFILIATED HOSPITAL OF SUN YAT SEN UNIV
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