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Preparation method of high-purity febuxostat

A febuxostat, high-purity technology, applied in the field of preparation of high-purity febuxostat, can solve problems such as difficult to remove and difficult to achieve product quality, and achieve quality safety, short reaction time, and simple operation.

Inactive Publication Date: 2013-04-03
CHINA RESOURCES SAIKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] In the process of using this route to develop febuxostat, it is frustrating to find that the product quality of febuxostat produced according to this process is difficult to meet the requirements of ICH guidelines, and there is an impurity in the product that is difficult to purify and remove
This impurity is still difficult to remove through known solvents and repeated recrystallization

Method used

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  • Preparation method of high-purity febuxostat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1: Preparation of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate

[0049] 1.1 Add 284g of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate, 200g of potassium carbonate, 1300ml of DMF, 64.3g of potassium iodide into a 5L reaction flask, stir, and heat up to Slowly add bromoisobutane 322g dropwise at 70-80°C, after the dropwise addition is complete, after reacting at 70-80°C for 20 hours, take a sample for TLC (sample is diluted with DMF, developing phase: ethyl acetate:petroleum ether=1:3; Stationary phase: GF254) to monitor the end of the reaction, cool to room temperature, add the reaction solution to 3.8L water, stir for 1 hour, and filter with suction to obtain 2-(3-formyl-4-isobutoxyphenyl)-4-methanol Ethylthiazole-5-carboxylate.

[0050] 1.2 Use distilled bromoisobutane (1-bromopropane content is less than 0.10%) to prepare 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester. Distillation co...

Embodiment 2

[0051] Embodiment 2: Preparation of febuxostat

[0052] Add 274g ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate and 1180ml pyrrolidone in a 5L reaction flask, add 162 g hydroxylamine hydrochloride, 527 g Na 2 SO 4 Heat to 130-140°C, keep for 24 hours, sample HPLC to monitor the reaction end point, after the reaction of the raw materials, cool to room temperature, put the reaction solution into 4L water, stir at room temperature for 1 hour, and filter with suction to obtain 2-(3-cyanide Crude ethyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate.

[0053] Add 200g ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate, 0.4LTHF and 0.4L ethanol, 0.8L1N sodium hydroxide solution into a 5L reaction flask, Stir and react at 30-35°C for 3 hours, sample TLC (developing phase: ethyl acetate: petroleum ether = 1:3; stationary phase: GF254) to monitor the end of the reaction, after the reaction of the raw materials is completed, the reaction liquid i...

Embodiment 3

[0054] Embodiment 3: the refining of febuxostat

[0055] Add 1.9L of acetone to the above crude product, reflux 4.3g of activated carbon and stir for 1h, filter while hot, stir and cool the filtrate below 15°C, filter with suction, add 1.2L of acetone to the obtained wet product, heat to reflux, stir for 0.5h, and cool to Stir at 25°C for 1 hour, filter with suction, and air-dry the obtained product at 65°C for 24 hours to obtain the finished febuxostat product with a yield of 63%.

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Abstract

The invention relates to a preparation method of high-purity febuxostat. The method comprises the steps: carrying out etherification reaction on ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate and refined bromo-isobutane, then conducting cyaniding and hydrolysis to obtain other crude febuxostat, and recrystalizing to obtain high-purity febuxostat. In febuxostat prepared by using the method, the content of impurity 2-(3-cyano-4-n-propoxy phenyl)-4-methylthiazole-5-formic acid is smaller than 0.10%.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a preparation method of high-purity febuxostat. Background technique [0002] Gout has become a common disease in the world today, especially among middle-aged and elderly men. The cause of the disease is that the body produces too much uric acid and the ability of the kidneys to clear it decreases, resulting in the continuous accumulation of uric acid in the body and the formation of hyperuricemia. The generation of uric acid in the body is related to purine metabolism. In the final stage of purine metabolism, xanthine generates uric acid under the action of xanthine oxidase (XO). Inhibiting the activity of XO can effectively reduce the generation of uric acid. Therefore, the new anti The development of gout drugs has always been a hot spot in drug research. [0003] Febuxostat (structural formula 1), chemical name 2-[3-cyano-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylic acid...

Claims

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Application Information

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IPC IPC(8): C07D277/56
Inventor 吕会超邹江杨琰
Owner CHINA RESOURCES SAIKE PHARMA
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