CN101817801A - Preparation method of new crystal form K of 2-(3-cyano-4-isobutoxy)-4-methyl-5-thiazole formic acid and other crystal forms - Google Patents
Preparation method of new crystal form K of 2-(3-cyano-4-isobutoxy)-4-methyl-5-thiazole formic acid and other crystal forms Download PDFInfo
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- CN101817801A CN101817801A CN200910090859A CN200910090859A CN101817801A CN 101817801 A CN101817801 A CN 101817801A CN 200910090859 A CN200910090859 A CN 200910090859A CN 200910090859 A CN200910090859 A CN 200910090859A CN 101817801 A CN101817801 A CN 101817801A
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Abstract
The invention relates to a crystal form K of 2-(3-cyano-4-isobutoxy)-4-methyl-5-thiazole formic acid obtained by taking ethyl acetate and petroleum ether as a mixed solvent and a preparation method thereof. The mixed solvent containing the ethyl acetate and the petroleum ether can also obtain the crystal form.
Description
Technical field
The present invention relates to a kind of crystal formation of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid and preparation method thereof.
Background technology
2-(3-the cyano-4-isobutoxy phenyl)-general Febuxostat by name of 4-methyl-5-thiazole formic acid (Febuxostat) is mainly used in the treatment of the too high relative disease of blood uric acid.
Febuxostat has multiple crystal formation, and Chinese patent CN1275126 has announced by the A that relates to this compound, the B of Japanese Supreme Being people company invention, C, D, G and amorphous and preparation method thereof.Wherein, crystal A is metastable crystal formation; Crystal D is a methylate; Crystal G is a hydrate.This piece patent adopts the solvent system crystal formation crystallization of methanol or isopropanol, and can transform according to different drying means crystal formation crystal formations.Chinese patent CN1970547 has announced by the H that relates to this compound, the I of Chongqing Inst. of Pharmaceutical Industry's invention, the preparation method of J.Reflection angle 2 θ of the X-ray powder diffraction pattern of these three kinds of crystal formations have charateristic avsorption band at about 6.71,7.19,10.03,11.10,12.96,13.48,15.78,17.60 and 22.15 places.In addition, Chinese patent CN101139325 has announced by the I that relates to this compound of Shanghai Institute of Pharmaceutical Industry's invention and the preparation method of II.The X-ray powder diffraction pattern of I and II N-type waferN has the characteristic absorbance that itself and other crystal formation tagma branch can be come.
Summary of the invention
The object of the present invention is to provide a kind of crystal formation of new Febuxostat, i.e. crystal form K.Another object of the present invention is to provide the method for preparing the Febuxostat crystal formation.
The feature of Febuxostat crystal form K:
Reflection angle 2 θ of its X-ray powder diffraction figure are 5.65 ± 0.2,7.91 ± 0.2,11.52 ± 0.2,12.77 ± 0.2,14.29 ± 0.2,15.42 ± 0.2,16.75 ± 0.2,17.44 ± 0.2,18.14 ± 0.2,18.39 ± 0.2,20.47 ± 0.2,20.98 ± 0.2,22.23 ± 0.2,23.31 ± 0.2,23.81 ± 0.2,24.45 ± 0.2,25.89 ± 0.2,26.08 ± 0.2,28.92 ± 0.2,31.26 ± 0.2,34.41 ± 0.2 (± 0.2 is the acceptable limit of error of 2 θ values).Its X-ray powder diffraction is seen Fig. 1.
Crystal form K is the mixed solvent with Febuxostat and ethyl acetate and sherwood oil, and perhaps after the mixed solvent heating for dissolving of ethyl acetate and normal hexane, recrystallization obtains.In ethyl acetate and sherwood oil system, the consumption of ethyl acetate is 10～50 times of Febuxostat, preferred 18 times; The consumption of sherwood oil is 1～5 times of Febuxostat, preferred 2 times; Heat required temperature and be about 20～80 ℃, preferred 65 ℃; Drying temperature is 60 ℃.In ethyl acetate and normal hexane system, the consumption of ethyl acetate is 10～50 times of Febuxostat, preferred 20 times; The consumption of normal hexane is 1～5 times of Febuxostat, preferred 1.5 times; Heat required temperature and be about 20～80 ℃, preferred 70 ℃; Drying temperature is 60 ℃.
The present invention also by different crystallization method obtained with Chinese patent CN101139325 in crystal form B, D conform among crystal formation I and the Chinese patent CN1275126 crystal formation.
Description of drawings
The accompanying drawing that comprises among the application is a component part of specification sheets, and accompanying drawing and specification sheets and claims one are used from explanation flesh and blood of the present invention, are used for better understanding the present invention.
Fig. 1 is the X-ray powder diffraction spectrum of Febuxostat crystal form K;
Fig. 2 is the X-ray powder diffraction spectrum of Febuxostat crystal formation I;
Fig. 3 is the X-ray powder diffraction spectrum of Febuxostat crystal form B;
Fig. 4 is the X-ray powder diffraction spectrum of Febuxostat crystal formation D;
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment do not constitute any restriction to the present invention.The analytical instrument that the following example adopted is following model:
Tianjin, X-ray:Cu island XRD-700/40Kv/30mA fusing point instrument: Shen light WRR fusing point instrument
Embodiment 1
The preparation method of Febuxostat crystal form K:
Reflux in the mixed solvent with Febuxostat 2.0g adding ethyl acetate 41ml and sherwood oil 7ml and dissolve, leave standstill then and be chilled to room temperature, after 4 hours, filter.60 ℃, 0.095MPa vacuum-drying 2 hours.Obtain crystal form K sample 1.4g.209～210 ℃ of fusing points.
Embodiment 2
The preparation method of Febuxostat crystal form K:
Reflux in the mixed solvent with Febuxostat 2.0g adding ethyl acetate 44ml and normal hexane 4ml and dissolve, leave standstill then and be chilled to room temperature, after 4 hours, filter.60 ℃, 0.095MPa vacuum-drying 2 hours.Obtain crystal form K sample 1.3g.209～210 ℃ of fusing points.
Embodiment 3
The preparation method of Febuxostat crystal formation I:
Reflux in the mixed solvent with Febuxostat 1.0g adding butanone 8ml and normal hexane 4ml and dissolve, leave standstill then and be chilled to room temperature, after 2 hours, filter.60 ℃, 0.095MPa vacuum-drying 2 hours.Obtain crystal formation I sample 0.72g.208～209 ℃ of fusing points.
X-ray powdery diffractometry 2 θ are 6.56,7.24,12.86,13.28,16.17,16.51,17.45,18.98,20.86,21.96,23.06,23.83,24.68,25.87,26.73.
Embodiment 4
The preparation method of Febuxostat crystal form B:
Reflux in the mixed solvent with Febuxostat 1.0g adding butanone 2ml and methyl alcohol 4ml and dissolve, leave standstill then and be chilled to room temperature, after 4 hours, filter.50 ℃, 0.095MPa vacuum-drying 2 hours.Obtain crystal form B sample 0.65g.207～209 ℃ of fusing points.
X-ray powdery diffractometry 2 θ are 6.81,8.27,9.60,11.58,12.19,13.64,14.84,15.83,16.36,17.29,19.54,20.61,21.47,23.33,24.79,25.25,25.85,26.19,26.72,27.78,29.30.
Embodiment 5
The preparation method of Febuxostat crystal formation D:
Reflux in the mixed solvent with Febuxostat 1.0g adding ethanol 6ml and normal hexane 4ml and dissolve, leave standstill then and be chilled to room temperature, after 4 hours, filter.60 ℃, 0.095MPa vacuum-drying 2 hours.Obtain crystal formation D sample 0.78g.207～209 ℃ of fusing points.
X-ray powdery diffractometry 2 θ are 6.58,7.15,8.09,9.61,11.68,12.88,17.16,19.17,21.69,23.52,23.83,25.91,26.91,28.36,29.06,30.12,31.32.
Claims (8)
1. the crystal form K of a 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid, it is characterized in that: reflection angle 2 θ of this crystalline X-ray powder diffraction figure are 5.65 ± 0.2,7.91 ± 0.2,11.52 ± 0.2,12.77 ± 0.2,14.29 ± 0.2,15.42 ± 0.2,16.75 ± 0.2,17.44 ± 0.2,18.14 ± 0.2,18.39 ± 0.2,20.47 ± 0.2,20.98 ± 0.2,22.23 ± 0.2,23.31 ± 0.2,23.81 ± 0.2,24.45 ± 0.2,25.89 ± 0.2,26.08 ± 0.2,28.92 ± 0.2,31.26 ± 0.2, there is charateristic avsorption band at 34.41 ± 0.2 places.
2. crystal form K as claimed in claim 1 is characterized in that, the fusing point of described crystal formation is 209～210 ℃.
3. the preparation method of the crystal form K of a 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid, by crystalline method that described compound heating for dissolving is laid equal stress on, obtain product after filtering vacuum-drying, it is characterized in that using ethyl acetate and sherwood oil to make mixed solvent.
4. preparation method as claimed in claim 3 comprises the following steps:
With the mixed solvent recrystallization of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid with ethyl acetate and sherwood oil, the consumption of ethyl acetate is 10～50 times of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid weight, and the consumption of sherwood oil is 1～5 times of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid weight; Heating temperature required is 20～80 ℃; Drying temperature is 60 ℃.
5. preparation method as claimed in claim 4, it is characterized in that, the consumption of ethyl acetate is 18 times of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid weight, and the consumption of sherwood oil is 2 times of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid weight; Heating temperature required is 65 ℃; Drying temperature is 60 ℃.
6. the preparation method of the crystal form K of a 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid, by crystalline method that described compound heating for dissolving is laid equal stress on, obtain product after filtering vacuum-drying, it is characterized in that using ethyl acetate and normal hexane to make mixed solvent.
7. preparation method as claimed in claim 6 comprises the following steps:
With the mixed solvent recrystallization of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid with ethyl acetate and normal hexane, the consumption of ethyl acetate is 10～50 times of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid weight, and the consumption of normal hexane is 1～5 times of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid weight; Heating temperature required is 20～80 ℃; Drying temperature is 60 ℃.
8. preparation method as claimed in claim 7, it is characterized in that, the consumption of ethyl acetate is 20 times of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid weight, and the consumption of normal hexane is 1.5 times of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid weight; Heating temperature required is 70 ℃; Drying temperature is 60 ℃.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8415481B2 (en) | 2009-06-10 | 2013-04-09 | Teva Pharmaceuticals Usa, Inc. | Crystalline form of febuxostat |
| WO2013076738A2 (en) | 2011-11-15 | 2013-05-30 | Mylan Laboratories Ltd | Process for the preparation of febuxostat polymorphs |
| US8946441B2 (en) | 2010-06-25 | 2015-02-03 | Sandoz Ag | Polymorphs of an active pharmaceutical ingredient |
| US20150141658A1 (en) * | 2010-04-29 | 2015-05-21 | Dr. Reddy's Laboratories Ltd. | Preparation of febuxostat |
| WO2016091230A1 (en) | 2014-12-12 | 2016-06-16 | Zentiva, K.S. | Formulations containing a solid solution of febuxostat |
| CN107540630A (en) * | 2016-06-29 | 2018-01-05 | 康普药业股份有限公司 | A kind of Febustat compound and preparation method |
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| CN101386605A (en) * | 2008-10-23 | 2009-03-18 | 中国科学院上海药物研究所 | Febustat novel crystal and preparation method thereof |
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| CN101497589A (en) * | 2009-02-26 | 2009-08-05 | 沈阳药科大学 | Method for synthesizing 2-(3-cyano-4- isobutoxy phenyl)-4-methyl-carboxylate |
| CN101684107A (en) * | 2008-09-26 | 2010-03-31 | 上海优拓医药科技有限公司 | New febuxostat crystal form and preparing method thereof |
| CN101781270A (en) * | 2009-01-20 | 2010-07-21 | 重庆医药工业研究院有限责任公司 | High-purity Febuxostat and preparation method thereof |
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| US8742129B2 (en) | 2009-06-10 | 2014-06-03 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of febuxostat |
| US8415481B2 (en) | 2009-06-10 | 2013-04-09 | Teva Pharmaceuticals Usa, Inc. | Crystalline form of febuxostat |
| US8609856B2 (en) | 2009-06-10 | 2013-12-17 | Teva Pharmaceuticals Usa, Inc. | Crystalline forms of Febuxostat |
| US20150141658A1 (en) * | 2010-04-29 | 2015-05-21 | Dr. Reddy's Laboratories Ltd. | Preparation of febuxostat |
| EP2585445B1 (en) * | 2010-06-25 | 2015-08-19 | Sandoz AG | Polymorphs of an active pharmaceutical ingredient |
| US8946441B2 (en) | 2010-06-25 | 2015-02-03 | Sandoz Ag | Polymorphs of an active pharmaceutical ingredient |
| EP2977372A1 (en) * | 2010-06-25 | 2016-01-27 | Sandoz Ag | Polymorphs of febuxostat |
| CN104114545A (en) * | 2011-11-15 | 2014-10-22 | 迈兰实验室有限公司 | Process for the preparation of febuxostat polymorphs |
| JP2014533297A (en) * | 2011-11-15 | 2014-12-11 | マイラン ラボラトリーズ リミテッドＭｙｌａｎ Ｌａｂｏｒａｔｏｒｉｅｓ Ｌｉｍｉｔｅｄ | Process for the preparation of polymorphs of febuxostat |
| WO2013076738A3 (en) * | 2011-11-15 | 2013-10-10 | Mylan Laboratories Ltd | Process for the preparation of febuxostat polymorphs |
| WO2013076738A2 (en) | 2011-11-15 | 2013-05-30 | Mylan Laboratories Ltd | Process for the preparation of febuxostat polymorphs |
| WO2016091230A1 (en) | 2014-12-12 | 2016-06-16 | Zentiva, K.S. | Formulations containing a solid solution of febuxostat |
| CN107540630A (en) * | 2016-06-29 | 2018-01-05 | 康普药业股份有限公司 | A kind of Febustat compound and preparation method |
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