Synthesis process of febuxostat

A technology of febuxostat and synthesis process, which is applied in the field of febuxostat synthesis process, can solve the problems of high operational risk, high production cost, and unsuitability for industrial production, and achieve safe operation, high purity of intermediate products, and improved The effect of product purity

Pending Publication Date: 2020-08-07
EMEISHAN HONGSHENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved by the present invention is that the original synthetic route of febuxostat uses highly toxic cuprous cyanide and potassium cyanide, the overall process production cost is high, the operation is dangerous, and it is not suitable for industrial production. The purpose is to provide febuxostat The synthetic process of Sestat solves the problem that the original synthetic route of febuxostat uses highly toxic cuprous cyanide and potassium cyanide

Method used

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  • Synthesis process of febuxostat
  • Synthesis process of febuxostat
  • Synthesis process of febuxostat

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] The synthetic technique of febuxostat of the present invention comprises the following steps:

[0027] S1. Preparation of 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5 from ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate - ethyl formate;

[0028] S2, 2-(3-formyl-4-isobutoxyphenyl)-4- Ethyl methylthiazole-5-carboxylate;

[0029] S3, prepare 2-(3-cyano-4-isobutoxyphenyl) with ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate - ethyl 4-methylthiazole-5-carboxylate;

[0030] S4, preparing febuxostat crude product with ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate;

[0031] S5. The pure product of febuxostat is obtained by monocrystalline the crude product of febuxostat, and the pure product of febuxostat is the target product.

[0032] Synthetic route such as figure 1 As shown, the present invention uses raw materials different from the original synthetic route, without using highly toxic cuprous cyanide and potassium ...

Embodiment 2

[0034] Based on Example 1, the specific steps of S1 are as follows: according to the amount of feed in Table 1, add polyphosphoric acid and phosphoric acid in turn in the reaction tank, start stirring and heating, and add 2-(4-hydroxyphenyl)- Ethyl 4-methylthiazole-5-carboxylate and urotropine, control the heating rate, slowly raise the temperature to 60-90°C, stir and dissolve completely, keep warm for about 2-6 hours, take samples for testing, after the reaction is completed, cool down Add 10L of drinking water after the temperature is below 30°C, stir for 1 hour, cool down to 0-5°C, centrifuge, wash the filter cake twice with drinking water, put the filter cake in a blast drying oven, and dry it at 50-80°C. Obtain 340-360 g of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate with a purity of ≥98%.

[0035] Table 1 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-formic acid ethyl ester preparation dosage

[0036] Material name Feed amount (g) ...

Embodiment 3

[0038] Based on the above examples, the specific steps of S2 are as follows: according to the amount of feed in Table 2, add DMF or DMSO in the reaction tank, start stirring, add 2-(3-formyl-4-hydroxyphenyl)-4-methanol Ethylthiazole-5-carboxylate, stir to dissolve, add anhydrous potassium carbonate or sodium carbonate, stir and add bromoisobutane dropwise, dropwise for 1~3h, keep the temperature at 30~60°C, after the dropwise addition, Slowly raise the temperature to 70-100°C, keep it warm for 2-3 hours, after the reaction is completed, start adding hydrochloric acid dropwise, check the pH value, stop adding hydrochloric acid when the pH is between 7-8, turn on the cold brine and cool down to -5-5°C, Stir and crystallize for 2h, centrifuge, wash, and dry the filter cake at 60-70°C to obtain ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate 380- 400g, the purity is greater than 98.0%.

[0039] Table 2 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-formic a...

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Abstract

The invention discloses a synthesis process of febuxostat. The synthesis process comprises the following steps: taking ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate as a raw material to prepare ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5- formate; preparing ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-formate from the ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-formate; preparing ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-formate from ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-formate; preparing a crude febuxostat product fromethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-formate; and specifically crystallizing the febuxostat crude product to prepare a febuxostat pure product, wherein the febuxostat pure product isa target product. The method solves the problems that an original synthesis route is high in operation risk and not suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis process, in particular to a synthesis process of febuxostat. Background technique [0002] Febuxostat is a xanthine oxidase (XO) inhibitor, which is suitable for the long-term treatment of hyperuricemia with gout symptoms; the main component of febuxostat is febuxostat, and its chemical structural formula is: [0003] [0004] The original research patent JP2725886 discloses the original research synthesis route of febuxostat, but the whole route uses noble metal catalytic hydrogenation, diazo reaction and other dangerous reactions, and uses highly toxic cuprous cyanide and potassium cyanide when introducing cyano groups. Therefore, the production cost of the overall process is high, the operation risk is high, and it is not suitable for industrialized production. Contents of the invention [0005] The technical problem to be solved by the present invention is that the original synthetic route of febuxostat us...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 鲁成宪
Owner EMEISHAN HONGSHENG PHARMA
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