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Preparation method of Febuxostat

A febuxostat and methyl technology, applied in the field of preparation of febuxostat, can solve the problems of high cyanide quality control requirements, operator and environmental hazards, product purity, low yield, etc., and achieve mild reaction conditions , improve the purity and yield, suitable for industrial production

Active Publication Date: 2019-02-12
KUNMING YUANRUI PHARMA
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Problems solved by technology

2) No highly toxic substances are used in the route one, and the impurities in the product can be more effectively controlled. The cyanide used in the route two is toxic, and the quality control requirements for the cyanide in the final product are also relatively high. The environment has great harm, which is not conducive to industrialized large-scale production
[0011] However, currently using Route 1 to synthesize febuxostat, the purity and yield of the obtained product are still low, and the impurities are difficult to control

Method used

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  • Preparation method of Febuxostat
  • Preparation method of Febuxostat
  • Preparation method of Febuxostat

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preparation example Construction

[0030] The invention provides a kind of preparation method of febuxostat, comprises the following steps:

[0031] (1) Mix 2-(3-formyl-4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, bromoisobutane, anhydrous potassium carbonate and DMF for isobutyl After the reaction is completed, cool the isobutylation reaction solution to 0-10°C, add water to quench the reaction, filter, wash and dry the resulting filter cake to obtain 2-(3-formyl-4-isobutyl Oxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester;

[0032] (2) After mixing the 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, formic acid, hydroxylamine hydrochloride and sodium formate, carry out cyanation Reaction, after the reaction is completed, cool the cyanation reaction solution to 0-10°C, add water to quench the reaction, filter and dry to obtain 2-(3-cyano-4-isobutoxyphenyl)-4- Methyl-thiazole-5-carboxylic acid ethyl ester;

[0033] (3) After mixing the 2-(3-cyano-...

Embodiment 1

[0070] (1) Intermediate 1: Synthesis of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-thiazole-5-carboxylate:

[0071] Add 250ml of N,N-dimethylformamide to the reaction flask, and add 50g of 2-(3-formyl-4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester successively under stirring, 58.78 g of bromoisobutane, and then add 71.16g of anhydrous potassium carbonate, after the addition is complete, heat to 80°C to react for about 8h, and it is yellow and turbid. TLC detected that the reaction was complete, lowered to room temperature, continued to lower to 0°C, quenched by adding ice water, heated up violently, slowly added ice water dropwise, the reaction solution became viscous, continued to stir for 30 minutes, suction filtered, and rinsed the vessel with an appropriate amount of water , and dried to obtain 56.7g of solid, the yield was 95.1%, and the purity was 98.2%.

[0072] Further purify the obtained product: prepare a mixed solution of EA and PE, mix the obt...

Embodiment 2

[0081] (1) step (1) is identical with embodiment 1

[0082] (2) Other conditions are the same as in Example 1, only changing the amount of hydroxylamine hydrochloride to 9.28g, to obtain 27.9g of solid, with a yield of 93.9%, and a purity of 99%, without further purification (the same as that of step (2) in Example 1) Conclusion, 99% pure, no further purification required).

[0083] (3) Other conditions were the same as in Example 1, except that the reaction temperature was changed to 40° C. to obtain 23.1 g of a white solid with a yield of 89.8%.

[0084] (4) Other conditions were the same as in Example 1, except that the crystallization temperature was changed to 0° C. to obtain 69.2 g of white febuxostat finished product, with a purity of 99.7%, and a yield of 75.2%.

[0085] As can be seen from the above examples, the present invention greatly improves the purity and yield of the product and reduces the cost by post-processing the product of each step of the reaction, ref...

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Abstract

The invention provides a preparation method of Febuxostat, and belongs to the technical field of pharmaceutical synthesis. According to the method provided by the invention, with 2-(3-formyl-4-hydroxyphenyl)-4-methyl-thiazole-5-ethyl carboxylate as a raw material, the Febuxostat is synthesized through an isobutylation reaction, a cyanation reaction and a hydrolysis reaction. The synthesis route issimple; through aftertreatment of the product of each step of the reaction as well as refining for purification, crystal regulation and the like on crude products, the product purity and yield are remarkably improved, the cost is lowered, and the operation is easier and more reasonable; moreover, the preparation method provided by the invention has the advantages of mild reaction conditions and lower energy consumption and is more suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a preparation method of febuxostat. Background technique [0002] Gout is a heterogeneous disease characterized by increased blood uric acid due to purine metabolism disorder and uric acid excretion disorder, and a group of clinical syndromes in which urate (monosodium urate, MSU) crystals are deposited in tissues or organs and cause tissue damage. The main manifestations are recurrent joint redness, swelling, heat, pain and dysfunction, including hyperuricemia, recurrent gouty acute arthritis, characteristic chronic arthritis and joint deformity, often involving the kidneys and causing chronic intermittent Nephritis and uric acid stone formation. Febuxostat can be used to treat hyperuricemia. The mechanism of action is that febuxostat is a competitive xanthine oxidase inhibitor, which can reduce uric acid by inhibiting the synthesis of uric acid. At the same ti...

Claims

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Application Information

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IPC IPC(8): C07D277/56
CPCC07B2200/13C07D277/56
Inventor 王高华徐春霞牛树伟朱兴正
Owner KUNMING YUANRUI PHARMA
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