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Preparation method of 2-(3-cyan-4-isobutoxyphenyl)-4-methylthiazole-5-formic acid A crystal

A technology of isobutoxyphenyl and methylthiazole, which is applied in the field of preparation of crystal form A of 2--4-methylthiazole-5-carboxylic acid, can solve the limitations, and does not disclose the mixed solvent system's ability to remove impurities, etc. problem, to achieve the effect of strong purification effect

Active Publication Date: 2014-04-23
ZHEJIANG APELOA KANGYU PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the solvent residue guideline of ICH, it is stipulated that the solvents of the first class and the second class are not only lower in the limit of solvent residues, but also strictly restricted in practical application.
Some of the above-mentioned Chinese invention patents use the second type of solvent to prepare a certain crystal form, which is subject to certain restrictions in practical application
Japanese Teijin Co., Ltd. disclosed in the Chinese patent CN102471295 that the third type of solvent with low toxicity to the human body was used to prepare febuxostat A crystal bulk drug, but did not disclose the ability of the mixed solvent system to remove impurities

Method used

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  • Preparation method of 2-(3-cyan-4-isobutoxyphenyl)-4-methylthiazole-5-formic acid A crystal
  • Preparation method of 2-(3-cyan-4-isobutoxyphenyl)-4-methylthiazole-5-formic acid A crystal

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Add 6ml of n-propanol to 5.0g of febuxostat solid, heat to 85°C, add 50ml of isopropyl acetate, the solid is completely dissolved, then cool down to 0-5°C, filter the precipitated crystals and dry to obtain febuxostat Tan 4.24g, yield 84.8%, m.p=208.6~208.7℃. HPLC purity: 99.90%. Febuxostat ethyl ester was not detected. The febuxostat sample that is prepared is carried out XRPD and IR detection, and detection result is as follows figure 1 and figure 2 . The main peaks in the graph are shown in Table 1 below:

[0044] Table 1

[0045]

[0046] Depend on figure 1 As can be seen from Table 1, in the X-ray powder diffraction spectrogram of the sample, represented by reflection angle 2θ, it is roughly at 6.748, 7.329, 12.963, 13.441, 16.298, 16.653, 17.621, 19.164, 19.726, 20.868, 21.129, 22.094, 22.869, There are characteristic peaks at 23.191, 23.976, 24.433, 24.840, 25.683, 26.040, 26.860, 29.170, 31.013, 31.273, 36.686 and 38.433, which are basically consisten...

Embodiment 2

[0048] Add 40ml of isopropyl acetate to 5.0g of febuxostat solid, heat to reflux at 85°C, add 6ml of n-propanol, the solid is completely dissolved, then cool down to 20-25°C, filter the precipitated crystals and dry to obtain febuxostat 3.62 g, yield 72.4%, XRPD and IR showed that the obtained crystal was Form A (XRPD and IR detection results were the same as in Example 1), m.p=208.7-208.9°C. HPLC purity: 99.91%. Febuxostat ethyl ester was not detected.

Embodiment 3

[0050] Add 40ml of n-propyl acetate to 5.0g of febuxostat solid, heat to 95°C, add 2.5ml of n-propanol, the solid is completely dissolved, then cool down to -10~-5°C, filter the precipitated crystals and dry them to obtain febuxostat Buxostat 4.0g, yield 80.0%, XRPD and IR showed that the obtained crystals were crystal form A (XRPD and IR detection results were the same as in Example 1), m.p=208.5-208.6°C. HPLC purity: 99.93%. Febuxostat ethyl ester was not detected.

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Abstract

The invention discloses a preparation method of 2-(3-cyan-4-isobutoxyphenyl)-4-methylthiazole-5-formic acid A crystal. The preparation method comprises the following steps: mixing 2-(3-cyan-4-isobutoxyphenyl)-4-methylthiazole-5-formic acid with a solvent I and a solvent II, heating until the compound is completely dissolved, and cooling the solution to crystallize so as to obtain a febuxostat crystal; wherein the solvent I is one or more components selected from ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetone, and ethyl acetate; and the solvent II is one or more components selected from n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, and methyl tertbutyl ether. The preparation method has the advantages that: a febuxostat crystal can be prepared through the solvent system provided by the invention, and does not contain any impurity namely febuxostat acetate; moreover the solvents used in the system are all third-kind solvents with small toxicity, and thus the preparation method is environment-friendly.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for preparing crystal form A of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid. Background technique [0002] Febuxostat, CAS registration number is 144060-53-7, chemical name is 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid, chemical The structural formula is as formula (1): [0003] [0004] Formula (1): 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid [0005] Febuxostat is the first new type of high-efficiency selective inhibitor of non-purine xanthine oxidase, developed by Japan Teijin Co., Ltd. It was approved for marketing by the European Union in May 2008, and it was approved for marketing in the United States by the FDA in February 2009 , for the treatment of gout and hyperuricemia, is the first new drug approved for the treatment of gout patients with hyperuricemia in 40 years. [...

Claims

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Application Information

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IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 孙光周元敬刘思宏陈剑冯立春葛萌芽
Owner ZHEJIANG APELOA KANGYU PHARMA
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