Preparation method of teriflunomide

A technology of fluritamide and acetamide, applied in the field of preparation of fluritamide (Teriflunomide), can solve the problems of low yield, long route, unfavorable for actual production and the like, and achieves high yield, easy-to-obtain raw materials, The effect of mild reaction conditions

Inactive Publication Date: 2014-04-09
WUHAN INSTITUTE OF TECHNOLOGY
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  • Abstract
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  • Application Information

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Problems solved by technology

The route is long and the yield is low, w

Method used

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

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Embodiment 1

[0014] Preparation of intermediate cyanoacetyl chloride: In a three-necked flask, add 1.7g cyanoacetic acid (0.02mol), anhydrous ether 20mL, stir and dissolve, then add 8.3g phosphorus pentachloride (0.04 mol), at the beginning of addition, the reaction temperature rose rapidly, and then gradually stabilized at 10°C. After the addition was complete, stir for 1 hour. The reaction equation is as follows:

[0015]

[0016] Then the solvent was evaporated under reduced pressure, and the solution turned yellow. 20 mL of toluene was added, and the solvent was removed under reduced pressure to obtain a brown liquid. The intermediate was not purified and was used for future use.

[0017] Preparation of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide: Add 2.254g p-trifluoromethylaniline (0.014mol) and 10ml (0.126mol) of pyridine to the reaction flask, and anhydrous Take 20ml of diethyl ether, cool in an ice bath, add 1.22g (0.012mol) of cyanoacetyl chloride obtained in the previous...

Embodiment 2

[0025] The preparation of the cyanoacetyl chloride of embodiment 2 and the preparation of 2-cyano group-N-(4-trifluoromethyl-phenyl)-acetamide are the same as embodiment 1, difference is: the intermediate prepared in embodiment 1 Add 0.8g (0.0035mol) of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide to 10mL of acetonitrile, and add 1.42g (0.0141mol) of triethylamine under ice-bath conditions to complete the addition After cooling to -15°C, 0.444 g of acetyl chloride (0.0056 mol) was added dropwise. The reaction was violently exothermic, and the solution gradually turned reddish brown. After the addition of acetyl chloride, the ice bath was removed and the temperature was slowly raised to room temperature.

[0026] After reacting for 5 hours, the solution gradually turned light yellow, and was subjected to suction filtration, and the filter cake of the suction filtration was detected by TLC to have no product. The filtrate was adjusted to pH = 2 with 10% hydrochloric acid. Du...

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Abstract

The invention relates to a preparation method of teriflunomide. The preparation method comprises the following steps: mixing cyano acetyl chloride, p-trifluoromethylaniline and an acid-binding agent according to the molar ratio of 1:(1-3):(8-11), and reacting to obtain 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide; mixing 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide, acetyl chloride and an acid-binding agent according to the molar ratio of 1:(1-5):(1-5) of reaction materials, and reacting to obtain teriflunomide. The process has the advantages that the raw materials are easily available, the reaction condition is mild and the yield is high, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of Teriflunomide. technical background [0002] Teriflunomide, chemical name: (Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)-phenyl]-2-butenamide. It is a dihydroorotate dehydrogenase (DHODH) inhibitor developed by Sanofi-Aventis (France), which is a kind of rheumatoid arthritis treatment drug Leflunomide (Leflunomide) The active metabolite, fluotetamine, is an orally administered anti-inflammatory drug that blocks the proliferation of T and B cells and is used in the treatment of multiple sclerosis. At present, the known mechanism of action of this product includes preventing the de novo synthesis of pyrimidine in lymphocytes by inhibiting dihydroorotate dehydrogenase (DHODH), and interfering with the activity of tyrosine kinase. The drug has broad development prospects. [0003] At present, the industrial production of flutermide mainly involves the condensation of ethyl acetoacetate and triethyl orthofo...

Claims

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Application Information

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IPC IPC(8): C07C255/23C07C253/30
Inventor 巨修练杜嘉文邓艳丽
Owner WUHAN INSTITUTE OF TECHNOLOGY
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