CN101139325B - 2-(3-cyano-4-isobuoxy phenyl)4-methyl-5-thiazole aminic acid crystal and preparation method thereof - Google Patents
2-(3-cyano-4-isobuoxy phenyl)4-methyl-5-thiazole aminic acid crystal and preparation method thereof Download PDFInfo
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Abstract
The present invention discloses two crystal models and the preparation method of the anti-hyperuricemia drug 2-(3-ayano-4-isobuoxy phenyl)-4-methyl-5- thiazole acid. The preparation method of the crystal models commonly uses the low-toxicity ethanol, ethyl acetate or acetone as the solvent; the safety is relatively high. In addition, the hygroscopicity of the two crystal models is low in the high-humidity environment and the two crystal models are suitable for the steady pharmaceutical preparation.
Description
Technical field
Two kinds of crystal formations that the present invention relates to 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid with and preparation method thereof.
Background technology
The Febustat general by name (Febuxostat) of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid is mainly used in the treatment of hyperuricemia.
EP 513379 has reported the synthetic method of Febustat, has mentioned with ethyl alcohol recrystallization in the literary composition and has obtained the finished product, does not still tell about the problem of crystal formation.Put down in writing Febustat and have five kinds of crystal form As, B, C, D, G and a kind of amorphousness in Chinese patent CN1275126, wherein the A crystalline substance is wherein relative stable crystal formation, and the D crystalline substance is a methylate, and the G crystalline substance is a hydrate.This piece patent all adopts the solvent system of methanol or isopropanol to carry out crystallization, and can carry out the crystal formation conversion according to different drying meanss.
Summary of the invention
The object of the present invention is to provide the crystal formation of two kinds of new Febustat, i.e. crystal formation I and II.Another kind of purpose of the present invention is to provide the method for preparing Febuxostat crystal form.
The feature of Febuxostat crystal form I:
Its X-ray powder diffraction pattern is about at reflection angle 2 θ: 6.60 ± 0.2,7.20 ± 0.2,11.84 ± 0.2,12.82 ± 0.2,13.26 ± 0.2,16.46 ± 0.2,17.82 ± 0.2,19.04 ± 0.2,19.56 ± 0.2,21.94 ± 0.2,22.72 ± 0.2,23.80 ± 0.2,24.28 ± 0.2,24.68 ± 0.2,25.88 ± 0.2,26.68 ± 0.2,37.76 ± 0.2 (± 2 is the acceptable limit of error of 2 θ values, below identical).Its X-ray powder diffraction is seen Fig. 1.
The feature of Febuxostat crystal form II:
Its X-ray powder diffraction pattern is about at reflection angle 2 θ: 4.78 ± 0.2,6.82 ± 0.2,8.30 ± 0.2,9.58 ± 0.2,11.74 ± 0.2,13.74 ± 0.2,14.60 ± 0.2,15.92 ± 0.2,16.68 ± 0.2,17.56 ± 0.2,21.26 ± 0.2,23.64 ± 0.2,24.80 ± 0.2,25.20 ± 0.2,25.78 ± 0.2,26.08 ± 0.2,26.66 ± 0.2,28.66 ± 0.2,31.64 ± 0.2.Its X-ray powder diffraction is seen Fig. 2.
Crystal formation I is that recrystallization obtains with after Febustat and the ethyl acetate heating for dissolving.The consumption of ethyl acetate is 10～100 times of Febustat, preferred 40 times; Heat required temperature and be about 20～80 ℃, preferred 40 ℃.
Crystal form II is by with Febustat and ethanol, sodium hydroxide solution heating mixed dissolution, make its alkalize to pH be 8～9, be adjusted to acidity with hydrochloric acid soln then, pH is 2～3, makes compound crystal, obtains product behind the filtration drying.Consumption of ethanol is 10～40 times of Febustat weight in the said process, preferred 20～30 times; Heating temperature is 20～80 ℃, preferred 40 ℃; The used concentration of sodium hydroxide solution that alkalizes is 0.5mol/L～2.0mol/L, preferred 1.0mol/L; The concentration of the used hydrochloric acid of acidifying is 0.5mol/L～4mol/L, preferred 1.0mol/L.Drying condition is 20～80 ℃, preferred 50 ℃.
The used solvent of Chinese patent CN1275126 crystallization is the first alcohol and water, wherein methyl alcohol is bigger to the toxicity of human body, medicinal product requires to be less than 0.03% to the residual quantity of methyl alcohol, and generally adopt the very little ethanol of toxicity, ethyl acetate or acetone as solvent among the present invention, so security is than higher.
In addition, through the comparison of wettability test, Febuxostat crystal form I is the most stable under super-humid conditions, and crystal form II and D crystalline substance be water absorbability slightly, and the brilliant water absorbability of A is the strongest, and concrete data see the following form 1.
Table 1 is to place 24 hours each crystal formation water absorbability under 75% and 92.5% the condition in humidity:
As seen from Table 1, under the higher environment of humidity, crystal formation I provided by the invention and crystal form II, particularly crystal formation I are metastable form, and this character illustrates that it is suitable for making stabilised pharmaceutical.
The present invention has also obtained the crystal formation that conforms to crystal form A, B, D among the Chinese patent CN1275126 by different crystallization method.
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 understanding better the present invention.
Fig. 1 is the X-ray powder diffraction spectrum of Febuxostat crystal form I;
Fig. 2 is the X-ray powder diffraction spectrum of Febuxostat crystal form II;
Fig. 3 is the X-ray powder diffraction spectrum of Febuxostat crystal form A;
Fig. 4 is the X-ray powder diffraction spectrum of Febuxostat crystal form B;
Fig. 5 is the X-ray powder diffraction spectrum of Febuxostat crystal form 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:
X-ray：Cu?K-ALPHA1/40kV/60mA
Embodiment 1
The preparation method of Febuxostat crystal form I:
Febustat 1.7g is added ethyl acetate 30ml backflow dissolving, be chilled to room temperature under stirring then, after 2 hours, filter.Dried 2 hours for 60 ℃.Obtain crystal formation I sample 1.5g.208～209 ℃ of fusing points.
Embodiment 2
The preparation method of Febuxostat crystal form I:
Febustat 0.5g is added ethyl acetate 5ml backflow dissolving, be chilled to room temperature under stirring then, after 2 hours, filter .60 ℃ of oven dry 2 hours. obtain 208～209 ℃ of crystal formation I sample 0.4g. fusing points.
Embodiment 3
The preparation method of Febuxostat crystal form I:
Febustat 1.0g is added ethyl acetate 100ml be heated to 20 ℃ of dissolvings, be chilled to room temperature under stirring then, after 2 hours, filter.Dried 2 hours for 60 ℃.Obtain crystal formation I sample 0.9g.208～209 ℃ of fusing points.
Embodiment 4
The preparation method of Febuxostat crystal form II:
Sodium hydroxide solution 16ml, the ethanol 80ml of Febustat 4.0g and 1mol/L are mixed, be heated to 40 ℃, stirring and dissolving, pH value are 9.With 1mol/L hydrochloric acid 19ml, regulate pH to 2 after being cooled to 20 ℃, stirred 30 minutes, filter, washing was dried 24 hours, and was obtained the 3.6g white solid for 50 ℃.201～203 ℃ of fusing points.
Embodiment 5
The preparation method of Febuxostat crystal form II:
Sodium hydroxide solution 4ml, the ethanol 10ml of Febustat 1.0g and 1mol/L are mixed, be heated to 78 ℃, stirring and dissolving.With 1mol/L hydrochloric acid 5ml, stirred 30 minutes, to filter, washing was dried 24 hours, and was obtained the 0.9g white solid for 50 ℃.201～203 ℃ of fusing points.
Embodiment 6
The preparation method of Febuxostat crystal form II:
Sodium hydroxide solution 4ml, the ethanol 40ml of Febustat 1.0g and 1mol/L are mixed, be heated to 30 ℃, stirring and dissolving, pH value are 9.With 1mol/L hydrochloric acid 4ml, stirred 30 minutes, to filter, washing was dried 24 hours, and was obtained the 0.8g white solid for 50 ℃.201～203 ℃ of fusing points.
Embodiment 7
The preparation method of Febuxostat crystal form A:
With the dissolving of Febustat 2g and acetone 20ml reflux, stirring and crystallizing, be chilled to 20 ℃ after restir 1 hour, filter, washing with acetone, 60 ℃ of oven dry 24 hours the 1g white solid.Fusing point: 208～209 ℃.
Powder x-ray diffraction 2 θ are 6.64,7.2,12.84,13.26,16.52,19.62,21.98,22.76,25.92,26.72,29.20,36.74.
Embodiment 8
The preparation method of Febuxostat crystal form B:
With the dissolving of Febustat 2g and acetone 20ml reflux, be cooled to 60 ℃ and stirred 30 minutes, there is solid to separate out, stopped to heat the back restir 2.5 hours, filter 5ml washing with alcohol, 25 ℃ of vacuum-drying 3 hours.Obtain the 1.5g white solid.207～209 ℃ of fusing points.
Powder x-ray diffraction 2 θ are 4.90,6.68,7.26,11.64,12.18,12.86,13.36,16.20,16.48,19.10,19.64,21.02,22.00,22.80,23.06,23.88,24.78,25.92,26.76.
Embodiment 9
The preparation method of Febuxostat crystal form D:
Febustat 2g is added in the 13ml ethanol, after the dissolving that refluxes, be cooled to 5 ℃ with frozen water rapidly and stirred 2 minutes, filter, 25 ℃ of vacuum-drying 12 hours.Obtain white solid 1.4g, 207～209 ℃ of fusing points.
Powder x-ray diffraction 2 θ are 7.92,8.14,9.54,12.86,17.12,19.20,21.58,23.42,24.30,25.94,30.12,33.54.
Claims (4)
1. the crystal formation I of a 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid, this crystalline X-ray powder diffraction pattern is 6.60 ± 0.2,7.20 ± 0.2 at 2 θ, 11.84 ± 0.2,12.82 ± 0.2,13.26 ± 0.2,16.46 ± 0.2,17.82 ± 0.2,19.04 ± 0.2,19.56 ± 0.2,21.94 ± 0.2,22.72 ± 0.2,23.80 ± 0.2,24.28 ± 0.2,24.68 ± 0.2,25.88 ± 0.2,26.68 ± 0.2,37.76 ± 0.2.
2. crystal formation I as claimed in claim 1 is characterized in that, the fusing point of described crystal formation is 208～209 ℃.
3. the preparation method of the crystal formation I of the described 2-of claim 1 (3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid, obtain product by crystalline method that described compound heating for dissolving is laid equal stress on, it is characterized in that using ethyl acetate to make solvent, wherein the consumption of ethyl acetate is 10～100 times of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid weight; Heating required temperature is 20～80 ℃.
4. preparation method as claimed in claim 3 is characterized in that, the consumption of ethyl acetate is 40 times of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid weight; Heating required temperature is 40 ℃.
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| CN200610030935A CN101139325B (en) | 2006-09-07 | 2006-09-07 | 2-(3-cyano-4-isobuoxy phenyl)4-methyl-5-thiazole aminic acid crystal and preparation method thereof |
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Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101386605B (en) * | 2008-10-23 | 2010-09-08 | 中国科学院上海药物研究所 | Febustat novel crystal and preparation method thereof |
| CN101781270B (en) * | 2009-01-20 | 2013-03-27 | 重庆医药工业研究院有限责任公司 | High-purity Febuxostat and preparation method thereof |
| ES2395381T3 (en) | 2009-06-10 | 2013-02-12 | Teva Pharmaceutical Industries Ltd. | Crystal forms of Febuxostat |
| MX2011013946A (en) * | 2009-07-15 | 2012-01-25 | Teijin Pharma Ltd | Process for producing crystals of polymorphic 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazoleâcaboxylic acid by poor-solvent addition method. |
| CN103936689B (en) * | 2009-07-17 | 2016-08-17 | 北京利乐生制药科技有限公司 | 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid crystal forms and preparation method thereof |
| WO2011080651A2 (en) | 2009-12-31 | 2011-07-07 | Ranbaxy Laboratories Limited | Polymorphic forms of febuxostat |
| CA2792036A1 (en) | 2010-03-04 | 2011-09-09 | Ranbaxy Laboratories Limited | Polymorph of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid |
| CN101824005B (en) * | 2010-04-27 | 2012-06-27 | 上海凯米侬医药科技有限公司 | New crystal form Q of Febuxostat and preparation method thereof |
| AR081267A1 (en) | 2010-07-13 | 2012-07-18 | Interquim Sa | PROCEDURE FOR OBTAINING THE CRYSTAL FORM A OF FEBUXOSTAT |
| TW201217347A (en) * | 2010-07-13 | 2012-05-01 | Interquim Sa | Process for preparing the crystalline form a of febuxostat |
| CN102442971B (en) * | 2010-10-13 | 2014-06-18 | 欣凯医药化工中间体（上海）有限公司 | Novel febuxostat crystal form and its preparation method |
| WO2012048861A1 (en) | 2010-10-14 | 2012-04-19 | Gador S.A. | A novel febuxostat crystalline form and the process for the preparation thereof |
| CN102267957B (en) * | 2011-08-24 | 2013-04-24 | 山东齐都药业有限公司 | Method for preparing Febuxostat crystal A |
| CA2855923A1 (en) * | 2011-11-15 | 2013-05-30 | Mylan Laboratories Ltd | Process for the preparation of febuxostat polymorphs |
| WO2013088449A1 (en) | 2011-12-16 | 2013-06-20 | Natco Pharma Limited | Stable crystal form of febuxostat and process for the preparation thereof |
| EP2692342A1 (en) | 2012-07-30 | 2014-02-05 | Interquim, S.A. | Process for the preparation of pharmaceutical compositions comprising febuxostat in the form of tablets |
| CN103396378B (en) * | 2013-07-29 | 2015-06-10 | 杭州朱养心药业有限公司 | Stable febuxostat crystal |
| CN103739568B (en) * | 2014-02-07 | 2015-09-16 | 浙江普洛康裕制药有限公司 | The preparation method of 2-(3-cyano-4-isobutoxy phenyl)-4-methylthiazol-5-formic acid A crystal formation |
| CN109776448B (en) * | 2019-03-13 | 2023-03-14 | 山东朗诺制药有限公司 | Preparation method of febuxostat crystal form A |
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| EP0513379B1 (en) * | 1990-11-30 | 1996-09-11 | Teijin Limited | 2-arylthiazole derivative and pharmaceutical composition containing the same |
| CN1275126A (en) * | 1998-06-19 | 2000-11-29 | 帝人株式会社 | Polymorphic modifications of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole-carboxylic acid and processes for the preparation thereof |
| CN1642546A (en) * | 2002-03-28 | 2005-07-20 | 帝人株式会社 | Solid preparation containing single crystal form |
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2006
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Patent Citations (3)
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| EP0513379B1 (en) * | 1990-11-30 | 1996-09-11 | Teijin Limited | 2-arylthiazole derivative and pharmaceutical composition containing the same |
| CN1275126A (en) * | 1998-06-19 | 2000-11-29 | 帝人株式会社 | Polymorphic modifications of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole-carboxylic acid and processes for the preparation thereof |
| CN1642546A (en) * | 2002-03-28 | 2005-07-20 | 帝人株式会社 | Solid preparation containing single crystal form |
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