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Preparation method of teriflunomide

A technology of teriflunomide and acetamide, which is applied in the field of preparation of teriflunomide, can solve the problems of unfavorable industrial production, corrosion of equipment, and low total yield

Inactive Publication Date: 2020-03-24
THE THIRD AFFILIATED HOSPITAL OF SUN YAT SEN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Most of existing teriflunomide synthetic methods need to use a large amount of acylating reagents, produce a large amount of smog and acid in the reaction, seriously corrode equipment and pollute air, on the other hand the synthetic intermediate product of these methods needs to purify, and total yield The rate is not high, which is not conducive to industrial production

Method used

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  • Preparation method of teriflunomide
  • Preparation method of teriflunomide
  • Preparation method of teriflunomide

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preparation example Construction

[0033] The invention provides a kind of preparation method of teriflunomide, comprises the following steps:

[0034] (1) Mix cyanoacetic acid, condensing agent, aprotic solvent and alkaline reagent, carry out condensation reaction, obtain active ester system;

[0035] (2) Mixing the active ester system with 4-trifluoromethylaniline for condensation reaction to obtain intermediate 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide;

[0036] (3) Mix the intermediate 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide with acetyl chloride for acylation reaction to obtain teriflunomide.

[0037] The invention mixes cyanoacetic acid, a condensing agent, an aprotic solvent and an alkaline reagent for condensation reaction to obtain an active ester system. In the present invention, the condensing agent is preferably CDI, Pybop, HATU, DCC, EDC.HCl, HOAt, HOBt, HCTU, TBTU or isobutyl chloroformate; the aprotic solvent is preferably acetone, acetonitrile, di Chloromethane, chloroform, carbon t...

Embodiment 1

[0052] (1) Dissolve 50g (0.59mol) cyanoacetic acid in 500mL dichloromethane and place in an ice bath; add 245g HATU (0.65mol) to the above reaction system and add 114.4g (1.6mol) N,N-diiso Propylethylamine was stirred in an ice bath for 1 hour to complete the condensation reaction, and the active ester system was obtained, which was directly used in the next step without purification and post-treatment.

[0053] (2) Add 100 g (0.62 mol) of 4-trifluoromethylaniline into the active ester system, stir at 0° C. for 3 h to carry out condensation reaction, and follow 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 light yellow solid was precipitated, filtered, the filter cake was washed with 500 mL of water, dried and weighed to obtain 110 g of the solid, with a yield of 82%.

[0054] The obtained light yellow solid compound is identified by p...

Embodiment 2

[0059] (1) Dissolve 50g (0.59mol) of cyanoacetic acid in 500mL of dichloromethane and place in an ice bath; add 368.4g (0.65mol) of PyBop into the above reaction system and add 161.9g (1.6mol) of triethylamine, ice After stirring in the bath for 1 h to complete the condensation reaction, the active ester system is obtained. This step does not require purification and post-treatment, and is directly used in the next reaction.

[0060] (2) With embodiment 1.

[0061] (3) 100g (0.44mol) of the intermediate 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide was dissolved in 1L of acetonitrile and placed in an ice bath, and 31.68g (1.32mol) was added for hydrogenation The sodium was reacted for 10 minutes, and then 41.5 g (0.53 mol) of acetyl chloride was added dropwise. After the drop was completed, the ice bath was removed, and the acylation reaction was carried out at a room temperature of 25° C., followed by TLC until the reaction of the raw materials was completed. After the reac...

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Abstract

The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of teriflunomide. The preparation method includes: (1) mixing cyanoacetic acid, a condensingagent, an aprotic solvent and an alkaline reagent, and carrying out condensation reaction to obtain an active ester system; (2) mixing the active ester system with 4-trifluoromethylaniline, and carrying out condensation reaction to obtain an intermediate 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide; and (3) mixing the intermediate 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide with acetyl chloride, and carrying out acylation reaction to obtain teriflunomide. According to the preparation method, cyanoacetic acid is reacted with 4-trifluoromethylaniline in the form of active ester, the reaction activity of cyanoacetic acid and 4-trifluoromethylaniline is improved, the reaction conditions are mild, the obtained active ester system can directly react with 4-trifluoromethylaniline without purification and post-treatment, the intermediate purification step is avoided, and the yield of teriflunomide is increased.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of teriflunomide. Background technique [0002] Teriflunomide, chemical name: (2Z)-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide, is an oral pyrimidine synthase Inhibitors and immunomodulators that can reverse inhibition of dihydroorotate dehydrogenase (DHODH). Teriflunomide is a new drug for the treatment of multiple sclerosis (MS) successfully developed by Sanofi-Aventis, which was approved by the US Food and Drug Administration (FDA) for marketing in September 2012 , for the treatment of adult relapsing multiple sclerosis. In-depth research on teriflunomide has also been 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...

Claims

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Application Information

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IPC IPC(8): C07C253/30C07C255/23
CPCC07C253/30C07D471/04C07D233/54
Inventor 邱伟汤有志陈晨张光雨
Owner THE THIRD AFFILIATED HOSPITAL OF SUN YAT SEN UNIV
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