CN103936689B - 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid crystal forms and preparation method thereof - Google Patents
2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid crystal forms and preparation method thereof Download PDFInfo
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- CN103936689B CN103936689B CN201410151385.1A CN201410151385A CN103936689B CN 103936689 B CN103936689 B CN 103936689B CN 201410151385 A CN201410151385 A CN 201410151385A CN 103936689 B CN103936689 B CN 103936689B
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- methylthiazol
- formic acid
- cyano
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- crystal formation
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- 239000013078 crystal Substances 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 title claims description 20
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 30
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 239000000843 powder Substances 0.000 claims description 13
- 238000010586 diagram Methods 0.000 claims description 7
- 238000010521 absorption reaction Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 230000008014 freezing Effects 0.000 claims description 2
- 238000007710 freezing Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- 238000002329 infrared spectrum Methods 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 6
- 229960000583 acetic acid Drugs 0.000 abstract description 3
- 239000012362 glacial acetic acid Substances 0.000 abstract description 3
- 201000001431 Hyperuricemia Diseases 0.000 abstract description 2
- 239000012046 mixed solvent Substances 0.000 abstract description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 abstract 1
- QMHIMXFNBOYPND-UHFFFAOYSA-N 4MTO Natural products CC1=CSC=N1 QMHIMXFNBOYPND-UHFFFAOYSA-N 0.000 abstract 1
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 abstract 1
- 235000019253 formic acid Nutrition 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 238000005755 formation reaction Methods 0.000 description 24
- 229960005101 febuxostat Drugs 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 3
- 238000005286 illumination Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- YZVFSQQHQPPKNX-UHFFFAOYSA-N 1,3-thiazole-5-carboxylic acid Chemical compound OC(=O)C1=CN=CS1 YZVFSQQHQPPKNX-UHFFFAOYSA-N 0.000 description 1
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 1
- MOQOOKGPCBQMCY-UHFFFAOYSA-N acetic acid;hexane Chemical compound CC(O)=O.CCCCCC MOQOOKGPCBQMCY-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention discloses crystal formation of three kinds of inhibiting hyperuricemia medicines 2 [3 cyano group 4 isobutoxy phenyl] 4 methylthiazol 5 formic acid and preparation method thereof.The preparation method of described crystal formation uses the common solvent such as ethyl acetate hexane mixed solvent, dichloromethane, glacial acetic acid, and prepared crystal formation does not has dissolvent residual, and safety is higher.
Description
The application is entitled " 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid crystal forms and preparation method thereof "
The divisional application of Chinese patent application CN200910160758.0.
Technical field
The present invention relates to 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid three kinds of novel crystal forms (I, II and
III) and preparation method thereof.
Background technology
The general entitled Febuxostat (Febuxostat) of 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid,
For a new generation's xanthine oxidase inhibitor, it is mainly used in the treatment of hyperuricemia clinically.
Febuxostat has multiple crystal formation, Chinese patent CN1275126 describe Febuxostat have five kinds of crystal formation A, B, C, D,
G and a kind of amorphous state, wherein crystal A is metastable-state crystal, and crystal B is that hydrate G drying under reduced pressure prepares, and crystal C leads to
Crossing the polymorphic inversion of solvent mediation, crystal D is methylate, and crystal G is hydrate.At Chinese patent CN970547
Describe Febuxostat and there are three kinds of crystal formations H, I and J.Describe Febuxostat at Chinese patent CN101139325 and there are two kinds
Crystal formation I and II.The present inventor is in the case of furtheing investigate, it was found that 2-[3-cyano-4-isobutoxy phenyl]-4-first
Three kinds of novel crystal forms of base thiazole-5-formic acid, these crystal formations are the most aqueous and solvent crystal habit, crystal formation be different from CN1275126,
Any one in crystal formation disclosed in CN970547 and CN101139325.
Summary of the invention
It is an object of the invention to provide 3 kinds of 2-[3-cyano-4-isobutoxy phenyl] crystal formation that-4-methylthiazol-5-formic acid is new.
The first 2-[3-cyano-4-isobutoxy phenyl] crystal formation that-4-methylthiazol-5-formic acid is new of the present invention, this crystal formation is fixed
Entitled I type, its X-ray powder diagram characteristic absorption peak angle of reflection 2 θ is about 7.3, and 14.7,16.6,18.3,26.0, see
Fig. 1.
The second 2-[3-cyano-4-isobutoxy phenyl] crystal formation that-4-methylthiazol-5-formic acid is new of the present invention, this crystal formation is fixed
Entitled II type, its X-ray powder diagram characteristic absorption peak angle of reflection 2 θ is about 5.7, and 8.6,12.1,14.4,24.2,25.0,
25.8, see Fig. 3.
The third 2-[3-cyano-4-isobutoxy phenyl] crystal formation that-4-methylthiazol-5-formic acid is new of the present invention, this crystal formation is fixed
Entitled type III, its X-ray powder diagram characteristic absorption peak angle of reflection 2 θ is about 5.6, and 7.8,11.5,12.6,20.4,20.9,
25.8, see Fig. 5.
In the present invention, the mensuration of 2 θ values uses CuK α light source, and precision is ± 0.2 °, therefore, and above-mentioned " X-ray powder diffraction
Figure characteristic absorption peak angle of reflection 2 θ be about " in " about " 2 θ ± 0.2 ° should be defined as, represent above-mentioned 2 taken θ values and allowed
Certain reasonably range of error, its range of error is ± 0.2 °.
It is another object of the present invention to disclose 2-[3-cyano-4-isobutoxy phenyl] crystal formation that-4-methylthiazol-5-formic acid is new
Preparation method.
The preparation method of 2-[3-the cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid crystal forms I of the present invention, its process
Including: it is 1: 5 that 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid is dissolved in mass volume ratio (grams per milliliter)
In the glacial acetic acid solvent of-1: 50, heating for dissolving, crystallize at 15-50 DEG C, filter, 100 DEG C are vacuum dried 6 hours,
To crystal formation I.
The preparation method of 2-[3-the cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid crystal forms II of the present invention, its process
Including: it is 1 that 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid is dissolved in mass volume ratio (grams per milliliter):
In the dichloromethane solvent of 25-1: 150, the dichloromethane solvent of preferably 1: 60, it is heated to reflux dissolving, crystallize under room temperature,
For obtaining higher yield, can freezing crystallize, filter, 40 DEG C are vacuum dried 6 hours, obtain crystal formation II.
The preparation method of 2-[3-the cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid crystal forms III of the present invention, its process
Including: it is 1: 5 that 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid is dissolved in mass volume ratio (grams per milliliter)
In the ethyl acetate solvent of-1: 50, heating for dissolving, add the normal hexane solvent of 1: 5-1: 50, crystallize under room temperature while hot.
Or the normal hexane-acetic acid second of 5-100 times of addition 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid weight
Ester mixed solvent (volume ratio 1: 1), heating for dissolving, crystallize under room temperature.Filtering, 80 DEG C are vacuum dried 6 hours, obtain crystalline substance
Type III.
Accompanying drawing explanation
Fig. 1 is the red of the I crystal of embodiment of the present invention 12-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid
External spectrum figure.
Fig. 2 is the X of the I crystal of embodiment of the present invention 12-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid
-x ray diffration pattern x.
Fig. 3 is the red of the II crystal formation of embodiment of the present invention 22-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid
External spectrum figure.
Fig. 4 is the X of the II crystal formation of embodiment of the present invention 22-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid
-x ray diffration pattern x.
Fig. 5 is the red of the III crystal formation of embodiment of the present invention 32-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid
External spectrum figure.
Fig. 6 is the X of the III crystal formation of embodiment of the present invention 32-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid
-x ray diffration pattern x.
Detailed description of the invention
The present invention can be conducted further description by the following examples, but, the invention of the present invention is not limited to following
Embodiment, these embodiments limit the scope of the present invention never in any form.Those skilled in the art is at the model of claim
Enclose interior some done change and adjustment also is regarded as belonging to the scope of the present invention.
Embodiment 1,
0.4g Febuxostat is placed in 10ml flask, adds glacial acetic acid 5ml, in 100 DEG C of oil bath heated and stirred to dissolving, treat
Raw material is completely dissolved, crystallize 2 hours at 20 DEG C, filters, and 100 DEG C are vacuum dried 6 hours, obtain crystalline powder.Survey
Fixed its X powder diffraction figure and infrared spectrogram, according to powder diagram and infrared spectrogram, generate crystal formation I, see Fig. 1 and Fig. 2.
Embodiment 2,
0.4g Febuxostat is placed in 50ml flask, adds dichloromethane 30ml, be heated to reflux to dissolving, treat that raw material is complete
Dissolving, crystallize 2 hours at 20 DEG C, filter, 40 DEG C are vacuum dried 6 hours, obtain crystalline powder.Measure its X powder
Diffraction pattern and infrared spectrogram, according to powder diagram and infrared spectrogram, generate crystal formation II, see Fig. 3 and Fig. 4.
Embodiment 3,
0.4g Febuxostat is placed in 50ml flask, adds ethyl acetate 10ml, in 80 DEG C of oil bath heated and stirred to dissolving,
Treat that raw material is completely dissolved, in 70 DEG C of lower dropping normal hexane 10ml of oil bath heating, crystallize 2 hours at 20 DEG C, filter, 80 DEG C
It is vacuum dried 6 hours, obtains crystalline powder.Measure its X powder diffraction figure and infrared spectrogram, according to powder diagram and red
External spectrum figure, generates crystal formation III, sees Fig. 5 and Fig. 6.
Embodiment 4,
Study on the stability
Taking I, II and III crystal of Febuxostat respectively, every kind of crystal point takes and is placed in numbered I1, II1 and III1 in right amount；
I2, II2 and III2, I3, II3 and III3 surface plate in, be stability test (condition 1:45001x ± 5001x respectively
Illumination, condition 2:60 DEG C high temperature, condition 3: relative humidity 75% high humidity), measurement result is as shown in the table
Table 1 strong illumination study on the stability
260 DEG C of high-temperature stabilities of table are investigated
Table 3 relative humidity 75% high humidity study on the stability
Claims (5)
1. a crystal formation II for 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid, its feature exists
It is 5.7 in the X-ray powder diagram of this crystal at angle of reflection 2 θ, 8.6,12.1,14.4,24.2,25.0,
Characteristic absorption peak is had at 25.8.
2. a preparation method of crystal formation II as claimed in claim 1, by laying equal stress on described compound heating for dissolving
The method of crystallization obtains product, it is characterised in that use dichloromethane is solvent.
3. preparation method as claimed in claim 2, it is characterised in that the consumption of solvent is that [3-cyano group-4-is different for 2-
Butoxy phenyl] 25-150 times of-4-methylthiazol-5-formic acid weight, it is heated to reflux dissolving, under room temperature or cold
Freeze lower crystallize.
4. preparation method as claimed in claim 3, it is characterised in that the consumption of solvent is 2-[3-cyano group-4-isobutyl
Phenyl] 60 times of-4-methylthiazol-5-formic acid weight, it is heated to reflux dissolving, under room temperature or freezing lower analysis
Brilliant.
5. crystal formation II as claimed in claim 1, it is characterised in that: infrared spectrum is 1684 and 1296cm-1Place has
Characteristic absorption peak.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410151385.1A CN103936689B (en) | 2009-07-17 | 2009-07-17 | 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid crystal forms and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910160758.0A CN101768150B (en) | 2009-01-05 | 2009-07-17 | 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid crystal forms and preparation method thereof |
| CN201410151385.1A CN103936689B (en) | 2009-07-17 | 2009-07-17 | 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid crystal forms and preparation method thereof |
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| CN200910160758.0A Division CN101768150B (en) | 2009-01-05 | 2009-07-17 | 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid crystal forms and preparation method thereof |
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| CN103936689B true CN103936689B (en) | 2016-08-17 |
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|---|---|---|---|---|
| US5614520A (en) * | 1990-11-30 | 1997-03-25 | Teijin Limited | 2-arylthiazole derivatives and pharmaceutical composition thereof |
| EP1020454A1 (en) * | 1998-06-19 | 2000-07-19 | Teijin Limited | Polymorphic modifications of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole-carboxylic acid and processes for the preparation thereof |
| CN1970547A (en) * | 2006-12-07 | 2007-05-30 | 重庆医药工业研究院有限责任公司 | Novel febuxostat crystal form and its preparation method |
| CN101085761A (en) * | 2007-06-29 | 2007-12-12 | 上海华拓医药科技发展股份有限公司 | Febuxotat microcrystal and compositions thereof |
| 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 |
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|---|---|---|---|---|
| JP3202607B2 (en) * | 1996-08-01 | 2001-08-27 | 帝人株式会社 | Method for producing 2- (4-alkoxy-3-cyanophenyl) thiazole derivative |
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|---|---|---|---|---|
| US5614520A (en) * | 1990-11-30 | 1997-03-25 | Teijin Limited | 2-arylthiazole derivatives and pharmaceutical composition thereof |
| EP1020454A1 (en) * | 1998-06-19 | 2000-07-19 | Teijin Limited | Polymorphic modifications of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazole-carboxylic acid and processes for the preparation thereof |
| 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 |
| 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 |
| CN1970547A (en) * | 2006-12-07 | 2007-05-30 | 重庆医药工业研究院有限责任公司 | Novel febuxostat crystal form and its preparation method |
| CN101085761A (en) * | 2007-06-29 | 2007-12-12 | 上海华拓医药科技发展股份有限公司 | Febuxotat microcrystal and compositions thereof |
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