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High-purity Febuxostat and preparation method thereof

A febuxostat, high-purity technology, applied in the field of medicinal chemistry, can solve problems such as impurities that are not easy to reduce or remove

Active Publication Date: 2010-07-21
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In order to overcome the deficiencies of the prior art and further improve the quality of febuxostat products and effectively control the impurities therein, the inventor prepared febuxostat with the method of patent JP10-45733, and studied the impurities therein. The research found that there are three relatively high impurities in the finished product of febuxostat, and these impurities are not easy to effectively reduce or remove by existing refining methods, such as recrystallization with methanol, ethanol, acetone and other solvents

Method used

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  • High-purity Febuxostat and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Preparation of 2-[3-carbamoyl-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZA)

[0055] In a 500ml three-necked flask, add 20.0g of ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylate, 10% hydrogen Dissolve 200ml of sodium oxide and 70ml of tetrahydrofuran, stir and react at 75-80°C for about 24 hours, cool, adjust the pH to about 3 with concentrated hydrochloric acid, and precipitate a white solid, filter, wash the filter cake with water, recrystallize with methanol, and collect by filtration Precipitate, the filter cake was dried under reduced pressure (-0.085~-0.090MPa) at 80~85°C to obtain 2-[3-carbamoyl-4-(2-methylpropoxy)phenyl]-4- Methyl-5-thiazolecarboxylic acid (FBZA) 9.4g, white crystal. HPLC purity: 98%. IR (KBr): 3464, 3399, 3190, 2963, 1693, 1646, 1598, 1505, 1411, 1256, 1161, 1016cm -1 . 1 H-NMR (500MHz, DMSO-d 6 )δ(ppm): 8.342~8.346(1H,d), 8.013~8.035(1H,m), 7.255~7.273(1H,d), 3.972~3.985(2H,d), 2.095~2.148(...

Embodiment 2

[0057] Preparation of 2-[3-carboxy-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZB)

[0058]In a 500ml three-necked bottle, 22.0g of ethyl 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylate, 10% sodium hydroxide Dissolve 220ml and 80ml tetrahydrofuran, heat to vigorous reflux, react for about 48 hours, stop heating, cool, slowly add concentrated hydrochloric acid dropwise, adjust pH to about 3, precipitate solid, filter with suction, wash the filter cake with water to neutral, and pump Dry. The filter cake was recrystallized with absolute ethanol, suction filtered, and the filter cake was dried under reduced pressure (-0.090~-0.095MPa) at 75-85°C to obtain 2-[3-carboxy-4-(2-methylpropoxy) Phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZB) 8.7g, off-white solid. HPLC purity: 98%. IR (KBr): 3396, 2959, 2874, 1692, 1604, 1508, 1422, 1377, 1293, 1252, 1223, 1167, 1111, 1092, 1017, 825cm -1 . 1 H-NMR (500MHz, DMSO-d 6 )δ(ppm): 8.185~8.181(...

Embodiment 3

[0060] Preparation of 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZC)

[0061] In a 500ml three-necked flask, add 28.0 g of ethyl 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylate, 10% hydrogen Dissolve 280ml of sodium and 90ml of ethanol, stir and react at about 80°C for about 4 hours, stop the reaction, cool, slowly add hydrochloric acid dropwise, adjust the pH to 3, precipitate a white solid, filter, wash the filter cake with water, and drain. The filter cake is recrystallized with ethyl acetate, filtered, and the filter cake is dried under reduced pressure (-0.080~-0.085MPa) at 70~75°C to obtain 2-[3-formyl-4-(2-methylpropoxy) 11.2 g of phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZC), white crystal. HPLC purity: 99%. IR (KBr): 3432, 2966, 2871, 1679, 1652, 1605, 1513, 1447, 1427, 1371, 1179, 1111, 1014cm -1 . 1 H-NMR (500MHz, DMSO-d 6 )δ(ppm): 13.360(1H, s), 10.397(1H, s), 8.191~8.153(2H, m), 7.337~7.319(1H,d), 3....

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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, in particular to a high-purity compound of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid (namely Febuxostat) and a preparation method thereof, wherein the purity thereof is not lower than 99.0%. The method uses a mixed solvent comprising two organic solvents to purify a Febuxostat crude product, and prepares a pharmaceutical composition by mixing a medical carrier and the high-purity compound.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to a compound containing 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (febuxostat) A high-purity compound, a method for preparing high-purity febuxostat, and a composition containing the high-purity febuxostat and pharmaceutical excipients. technical background [0002] The chemical name of Febuxostat is: 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid. The chemical structural formula is: [0003] [0004] Febuxostat is the first non-purine type of new xanthine oxidase inhibitor, which can safely and effectively treat diseases related to excessive uric acid, such as gout. Febuxostat has been approved for marketing in the European Union, and has also submitted a new drug registration to the US FDA, and has been approved and recommended. [0005] Patent WO92 / 09279 is the compound patent of the drug. The invention p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56A61K31/426A61P19/06
CPCC07D277/56A61K31/426A61P19/06
Inventor 周兴国唐雪民石瑞娜叶文润罗杰邓杰樊斌
Owner CHONGQING PHARMA RES INST
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