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Febuxostat intermediate preparation method

A technology of febuxostat and intermediates, applied in the field of preparation of intermediates, can solve the problems of poor reaction selectivity, difficult industrialization, complicated operation, etc., and achieves the effects of low industrialization cost, short route and high atom utilization rate

Inactive Publication Date: 2013-02-13
NOVASYNCS SUZHOU
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0037] The technical problem to be solved by the present invention is to provide a kind of febuxostat in order to overcome the defects such as poor reaction selectivity, high cost, complicated operation and difficult industrialization in the existing preparation method of the intermediate of febuxostat. The preparation method of the intermediate

Method used

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Experimental program
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Effect test

Embodiment 1

[0056] Embodiment 1: the preparation of 3-cyano group-4-isobutoxy thiobenzamide

[0057] In a 1L reaction flask, add 4-isobutoxy-1,3-benzenedicarbonitrile (20g, 0.1mol), and then add 420mL of isopropanol. After the system is dissolved and clarified, cool the system down to 10°C with an ice bath Slowly add 51 g of 40% ammonium sulfide aqueous solution (containing 20.4 g of ammonium sulfide, 0.3 mol) dropwise in a dropwise manner. After the dropwise addition is completed, stir the reaction at 10° C. to 15° C. until the disappearance of the raw materials is monitored by TLC or HPLC. After about 20 hours of reaction, the reaction was stopped. Evaporate the solvent under reduced pressure, then add 200 mL of ethyl acetate and 100 mL of water, stir and separate the layers, extract the water layer with 200 mL of ethyl acetate twice, combine the organic phases, wash with 100 mL of distilled water for 3 times, add anhydrous sodium sulfate to the organic phase After drying, the solvent ...

Embodiment 2

[0059] Embodiment 2; The preparation of 3-cyano-4-isobutoxy thiobenzamide

[0060] In a 1L reaction flask, add 4-isobutoxy-1,3-benzenedicarbonitrile (20g, 0.1mol), and then add 420mL of isopropanol. After the system is dissolved and clarified, the system is heated to 50°C to Slowly add 51g of 20% ammonium sulfide aqueous solution (containing 10.2g of ammonium sulfide, 0.15mol) dropwise. After the dropwise addition is completed, stir the reaction at 45°C to 50°C until the raw materials are monitored by TLC or HPLC. After 6 hours, the reaction stopped. Evaporate the solvent under reduced pressure, then add 200 mL of ethyl acetate and 100 mL of water, stir and separate the layers, extract the water layer with 200 mL of ethyl acetate twice, combine the organic phases, wash with 100 mL of distilled water for 3 times, add anhydrous sodium sulfate to the organic phase After drying, the solvent was evaporated under reduced pressure to obtain a crude product in the form of a yellow so...

Embodiment 3

[0062] Embodiment 3: the preparation of 3-cyano group-4-isobutoxy thiobenzamide

[0063] In a 1L reaction flask, add 4-isobutoxy-1,3-phthalonitrile (20g, 0.1mol), then add ethylene glycol dimethyl ether 420mL, triethylamine 30.4g, after the system is dissolved and clarified , the system was heated up to 50°C, and 34g of 20% ammonium sulfide aqueous solution (containing 6.8g of ammonium sulfide, 0.10mol) was slowly added dropwise in a dropwise manner. Alternatively, HPLC monitors the completion of the reaction, and stops the reaction after about 5 hours of reaction. Evaporate the solvent under reduced pressure, then add 200 mL of ethyl acetate and 100 mL of water, stir and separate the layers, extract the water layer with 200 mL of ethyl acetate twice, combine the organic phases, wash with 100 mL of distilled water for 3 times, add anhydrous sodium sulfate to the organic phase After drying, the solvent was evaporated under reduced pressure to obtain the crude product as a yell...

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Abstract

The present invention discloses a preparation method for a febuxostat intermediate represented by a formula III. The preparation method is characterized by comprising the following steps that: a compound represented by a formula II reacts with ammonium sulfide in an organic solvent and water, wherein a reaction temperature is 0-100 DEG C, and the organic solvent is one or a plurality of materials selected from an alcohol solvent, an ether solvent, a ketone solvent, dimethyl sulfoxide, an amide solvent and a nitrile solvent. The preparation method has characteristics of good reaction selectivity, simple post-treatment, high product yield and high product purity, and is suitable for industrialization.

Description

technical field [0001] The present invention specifically relates to a preparation method of an intermediate of febuxostat. Background technique [0002] Febuxostat was developed by Teijin Corporation of Japan. On May 5, 2008, Ipsen Company was approved by the European Union to be listed in France. It is a new type of non-purine xanthine oxidase inhibitor, which is clinically used to treat hyperuricemia (gout) . The structure is as follows [0003] [0004] The main related synthetic methods at home and abroad are: [0005] (1) WO9209279 [0006] [0007] This route takes 4-chloro-3-nitrobenzonitrile as raw material, reacts with isobutanol under the action of sodium hydride, then reacts with thioacetamide, and then cyclizes with ethyl 2-chloroacetoacetate, nitro Hydrogenation and reduction to amino groups, diazotization of amino groups, reaction with potassium cyanide, and finally hydrolysis and acidification to obtain febuxostat. [0008] This route is an earlier...

Claims

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Application Information

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IPC IPC(8): C07C327/48C07D277/56
Inventor 不公告发明人
Owner NOVASYNCS SUZHOU
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