CN102267957B - Method for preparing Febuxostat crystal A - Google Patents
Method for preparing Febuxostat crystal A Download PDFInfo
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- CN102267957B CN102267957B CN 201110243755 CN201110243755A CN102267957B CN 102267957 B CN102267957 B CN 102267957B CN 201110243755 CN201110243755 CN 201110243755 CN 201110243755 A CN201110243755 A CN 201110243755A CN 102267957 B CN102267957 B CN 102267957B
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Abstract
The invention belongs to the field of medicine chemistry and particularly relates to a method for preparing Febuxostat crystal A. The method comprises: dissolving, crystallizing and drying, wherein the dissolving is to dissolve Febuxostat in a solvent with heating in a water bath, the solvent may be RCOCH3 or RCH2OH, R may be methyl or ethyl, the mass/volume ratio of the Febuxostat to the solvent ranges from 1:5 to 1:20, the Febuxostat is based on gram and the volume of the solvent is based on milliliter; after dissolution, placing the solution in a water bath at 25 to 40 DEG C, standing, stirring for 20 to 40 minutes upon the precipitation of crystals; placing at -15 to 0 DEG C to continue to precipitate crystals for 8 to 10 hours, and filtering; and after filtering, drying at 65 DEG C under vacuum for 6 to 8 hours to obtain the Febuxostat crystal A. The Febuxostat crystal A prepared by the invention is high in purity and yield, the process is simple and easy to implement, the yield is 92.0 to 98.0 percent and the purity is more than 99.90 percent.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of preparation method of Febustat A crystal formation.
Background technology
Febustat (Febuxostat), its chemistry Febuxostat by name, its chemical structural formula is:
Febustat is ratified list marketing in European Union by EMEA in April, 2004, is ratified list marketing in the U.S. by FDA in February, 2009, for the long-term treatment of the hyperuricemia with gout symptom.Febustat has multiple crystal formation, and Chinese patent CN1275126 has put down in writing compound of the A that relates to this compound, B, C, D, G and unformed five kinds of crystal formations that the invention of Japanese Supreme Being people company is arranged and preparation method thereof; Chinese patent 200910118404.X has introduced H, I, three kinds of crystal formations of J and preparation method thereof.More Febuxostat crystal form is introduced in recent years, and wherein bibliographical information this product A crystal formation is relatively stable, and the stripping of tablet is better, therefore mainly the preparation of A crystal formation is studied in the research of Febustat sheet.Having introduced the method for preparing crystal A in patent CN1275126 is crystallization in a certain proportion of methanol aqueous solution, and the aqueous solution that needs to drip a certain amount of A crystal seed is induced separating out of crystal, and in this patent, do not mention yield and the purity of the A crystal formation of this method preparation, the inventor is in the preparation process according to this patent, can not realize certain circulation ratio, and consider methyl alcohol to the impact of environment, so further research has been carried out in the preparation of Febustat A crystal formation.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of Febustat A crystal formation, not only purity is high for the Febustat A crystal formation that makes, yield is high, and technique is simple, easy to implement.
The preparation method of described Febustat A crystal formation may further comprise the steps:
(1) dissolving: Febustat is dissolved in the solvent, the heating in water bath dissolving, solvent is RCOCH
3Or RCH
2OH, R are methyl or ethyl, and the Febustat quality is 1: 5～1: 20 with the solvent volume ratio, Febustat, and in gram, solvent volume is in milliliter;
(2) crystallization: dissolving is placed in 25～40 ℃ of water-baths leaves standstill, and when beginning to have crystal to separate out, stirs 20～40min, then is positioned over-15～0 ℃ of lower continuation crystallizatioies 8～10 hours, filters;
(3) drying: after the filtration, made in 6～8 hours in 55～65 ℃ of lower vacuum-dryings.
The described solvent of step (1) is acetone.
The described Febustat quality of step (1) is 1: 10～1: 15 with the solvent volume ratio, Febustat, and in gram, solvent volume is in milliliter.
Reflection angle 2 θ of the X-ray powder diffraction figure of the A crystal formation of preparing are at 6.62 ± 0.02 °, 7.21 ± 0.02 °, 12.84 ± 0.02 °, 13.31 ± 0.02 °, 16.53 ± 0.02 °, 19.61 ± 0.02 °, 21.98 ± 0.02 °, 22.73 ± 0.02 °, 25.90 ± 0.02 °, 26.74 ± 0.02 °, locate to have characteristic peak for 29.20 ± 0.02 ° and 36.74 ± 0.02 °.
The infrared spectra of the A crystal formation of preparing is at 1678 ± 1cm
-1With 1273 ± 1cm
-1There is charateristic avsorption band at the place.
Beneficial effect of the present invention is as follows:
Not only purity is high for the Febustat A crystal formation that the present invention makes, yield is high, and technique is simple, easy to implement, and yield is 92.0%～98.0%, purity 〉=99.90%.
Description of drawings
Fig. 1 is the infrared absorpting light spectra of embodiment 1 Febustat A crystal formation.
Fig. 2 is the X-ray powder diffraction figure of embodiment 1 Febustat A crystal formation.
Fig. 3 is the infrared absorpting light spectra of embodiment 2 Febustat A crystal formations.
Fig. 4 is the X-ray powder diffraction figure of embodiment 2 Febustat A crystal formations.
Fig. 5 is the infrared absorpting light spectra of embodiment 3 Febustat A crystal formations.
Fig. 6 is the X-ray powder diffraction figure of embodiment 3 Febustat A crystal formations.
Fig. 7 is the infrared absorpting light spectra of embodiment 4 Febustat A crystal formations.
Fig. 8 is the X-ray powder diffraction figure of embodiment 4 Febustat A crystal formations.
Embodiment
The invention will be further described below in conjunction with embodiment.
The infrared gear model is among the embodiment: the IRprestige-21 Fourier transformation infrared spectrometer; X diffractometer model is: PANalytical X ' Pert Pro powder x-ray diffraction; Purity adopts the HPLC area normalization method to calculate.
The 50g Febustat is placed the three-necked bottle of 1L, add 500ml acetone, heating in water bath refluxed 10 minutes, place 25 ± 2 ℃ water bath with thermostatic control to leave standstill reaction solution after the cooling, when beginning to have crystal to separate out, continue to stir 20min, stirring velocity is 600 ± 20 rev/mins, then reaction solution is put-10 ± 2 ℃ of lower freezing crystallizatioies 8 hours.Suction filtration.Filter cake in 60 ± 2 ℃ ,-0.08～-0.10MPa under vacuum-drying namely got the 47.7g crystal in 6 hours.Infrared detection is seen Fig. 1, at 1678cm
-1, 1273cm
-1There is characteristic peak at the place, and the X-diffraction the results are shown in Figure 2, and reflection angle 2 θ of the X-ray powder diffraction figure of the A crystal formation of preparing are at 6.64 °, 7.22 °, 12.86 °, 13.33 °, 16.54 °, 19.63 °, 21.99 °, 22.74 °, 25.91 °, 26.76 °, locate to have characteristic peak for 29.22 ° and 36.74 °.Confirm as A crystal formation Febustat.Yield is 95.4%, and purity is 99.98%.
Embodiment 2
The 50g Febustat is placed the three-necked bottle of 1L, 95% ethanol that adds 250ml, heating in water bath refluxed 10 minutes, place 30 ± 2 ℃ water-bath to leave standstill reaction solution after the cooling, after beginning have crystal to separate out, continue to stir 25min, stirring velocity is 600 ± 20 rev/mins, then reaction solution is put-12 ± 2 ℃ of lower freezing crystallizatioies 9 hours.Suction filtration.Filter cake in 60 ± 2 ℃ ,-0.08～-0.10MPa under vacuum-drying namely got the 47.3g crystal in 7 hours.Infrared detection is seen Fig. 3, at 1678cm
-1, 1274cm
-1There is characteristic peak at the place, and the X-diffraction the results are shown in Figure 4, and reflection angle 2 θ of the X-ray powder diffraction figure of the A crystal formation of preparing are at 6.63 °, 7.22 °, 12.84 °, 13.31 °, 16.54 °, 19.62 °, 22.00 °, 22.74 °, 25.92 °, 26.74 °, locate to have characteristic peak for 29.22 ° and 36.75 °.Confirm as A crystal formation Febustat.Yield is 94.6%, and purity is 99.96%.
Embodiment 3
The 50g Febustat is placed the three-necked bottle of 1L, add the 750ml butanone, heating in water bath refluxed 10 minutes, place 35 ± 2 ℃ water-bath to leave standstill reaction solution after the cooling, after beginning have crystal to separate out, continue to stir 30min, stirring velocity is 600 ± 20 rev/mins, then reaction solution is put-8 ± 2 ℃ of lower freezing crystallizatioies 10 hours.Suction filtration.Filter cake in 60 ± 2 ℃ ,-0.08～-0.10MPa under vacuum-drying namely got the 46.4g crystal in 8 hours.Infrared detection is seen Fig. 5, at 1678cm
-1, 1273cm
-1There is characteristic peak at the place, and the X-diffraction the results are shown in Figure 6, and reflection angle 2 θ of the X-ray powder diffraction figure of the A crystal formation of preparing are at 6.62 °, 7.20 °, 12.83 °, 13.30 °, 16.52 °, 19.60 °, 21.96 °, 22.71 °, 25.90 °, 26.73 °, locate to have characteristic peak for 29.19 ° and 36.73 °.Confirm as A crystal formation Febustat.Yield is 92.8%, and purity is 99.92%.
Embodiment 4
The 50g Febustat is placed the three-necked bottle of 1L, 95% propyl alcohol that adds 1000ml, heating in water bath refluxed 10 minutes, place 40 ± 2 ℃ water-bath to leave standstill reaction solution after the cooling, after beginning have crystal to separate out, continue to stir 40min, stirring velocity is 600 ± 20 rev/mins, then reaction solution is put-4 ± 2 ℃ of lower freezing crystallizatioies 10 hours.Suction filtration.Filter cake in 60 ± 2 ℃ ,-0.08～-0.10MPa under vacuum-drying namely got the 47.1g crystal in 8 hours.Infrared detection is seen Fig. 7, at 1678cm
-1, 1274cm
-1There is characteristic peak at the place, and the X-diffraction the results are shown in Figure 8, and reflection angle 2 θ of the X-ray powder diffraction figure of the A crystal formation of preparing are at 6.63 °, 7.22 °, 12.85 °, 13.33 °, 16.54 °, 19.62 °, 21.99 °, 22.74 °, 25.92 °, 26.75 °, locate to have characteristic peak for 29.21 ° and 36.74 °.Confirm as A crystal formation Febustat.Yield is 94.2%, and purity is 99.90%.
Claims (5)
1. the preparation method of a Febustat A crystal formation is characterized in that may further comprise the steps:
(1) dissolving: Febustat is dissolved in the solvent, the heating in water bath dissolving, solvent is RCOCH
3Or RCH
2OH, R are methyl or ethyl, and the Febustat quality is 1:5～1:20 with the solvent volume ratio, Febustat, and in gram, solvent volume is in milliliter;
(2) crystallization: dissolving is placed in 25～40 ℃ of water-baths leaves standstill, and when beginning to have crystal to separate out, stirs 20～40min, and then 15～0 ℃ of lower continuation crystallizatioies of Fang Zhi Yu – are 8～10 hours, filter;
(3) drying: after the filtration, made in 6～8 hours in 55～65 ℃ of lower vacuum-dryings.
2. the preparation method of Febustat A crystal formation according to claim 1, it is characterized in that: the described solvent of step (1) is acetone.
3. the preparation method of Febustat A crystal formation according to claim 1 is characterized in that: the described Febustat quality of step (1) and solvent volume be than being 1:10～1:15, Febustat, and in gram, solvent volume is in milliliter.
4. the preparation method of Febustat A crystal formation according to claim 1, it is characterized in that: reflection angle 2 θ of the X-ray powder diffraction figure of the A crystal formation of preparing are at 6.62 ± 0.02 °, and 7.21 ± 0.02 °, 12.84 ± 0.02 °, 13.31 ± 0.02 °, 16.53 ± 0.02 °, 19.61 ± 0.02 °, 21.98 ± 0.02 °, 22.73 ± 0.02 °, 25.90 ± 0.02 °, 26.74 ± 0.02 °, locate to have characteristic peak for 29.20 ± 0.02 ° and 36.74 ± 0.02 °.
5. according to claim 1 or the preparation method of 4 described Febustat A crystal formations, it is characterized in that: the infrared spectra of the A crystal formation of preparing is at 1678 ± 1cm
-1With 1273 ± 1cm
-1There is charateristic avsorption band at the place.
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| CN102267957B true CN102267957B (en) | 2013-04-24 |
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936688A (en) * | 2013-01-21 | 2014-07-23 | 上海华拓医药科技发展股份有限公司 | Preparation method of 2-(3-cyano-4-(2-methyl propoxy) phenyl)-4-methyl-5-thiazolecarboxylic acid crystal A |
| CN103588724B (en) * | 2013-09-10 | 2015-05-20 | 杭州华东医药集团新药研究院有限公司 | Febuxostat crystal form A and preparation method thereof |
| CN103467412B (en) * | 2013-09-30 | 2015-05-13 | 杭州朱养心药业有限公司 | Drug chemical compound for gout |
| 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 |
| CN110483441B (en) * | 2019-08-15 | 2023-02-28 | 迪嘉药业集团股份有限公司 | Preparation method of febuxostat crystal form A with low impurity content |
| WO2022014395A1 (en) * | 2020-07-13 | 2022-01-20 | 日本碍子株式会社 | Refining method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101139325A (en) * | 2006-09-07 | 2008-03-12 | 上海医药工业研究院 | 2-(3-cyano-4-isobuoxy phenyl)4-methyl-5-thiazole aminic acid crystal and preparation 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 |
| CA2764603A1 (en) * | 2009-07-15 | 2011-01-20 | Teijin Pharma Limited | Process for producing crystals of polymorphic 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid by poor-solvent addition method |
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| ES2395381T3 (en) * | 2009-06-10 | 2013-02-12 | Teva Pharmaceutical Industries Ltd. | Crystal forms of Febuxostat |
| JP5519201B2 (en) * | 2009-07-15 | 2014-06-11 | 光孝 北村 | Process for producing crystalline polymorph of 2- (3-cyano-4-isobutyloxyphenyl) -4-methyl-5-thiazolecarboxylic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101139325A (en) * | 2006-09-07 | 2008-03-12 | 上海医药工业研究院 | 2-(3-cyano-4-isobuoxy phenyl)4-methyl-5-thiazole aminic acid crystal and preparation 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 |
| CA2764603A1 (en) * | 2009-07-15 | 2011-01-20 | Teijin Pharma Limited | Process for producing crystals of polymorphic 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid by poor-solvent addition method |
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| JP特开2011-20950A 2011.02.03 |
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