CN102977039A - Alpha crystal form of 6-fluo-3-hydroxyl-2-pyrazinecarboxamide and preparation method thereof - Google Patents
Alpha crystal form of 6-fluo-3-hydroxyl-2-pyrazinecarboxamide and preparation method thereof Download PDFInfo
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- CN102977039A CN102977039A CN2012105355129A CN201210535512A CN102977039A CN 102977039 A CN102977039 A CN 102977039A CN 2012105355129 A CN2012105355129 A CN 2012105355129A CN 201210535512 A CN201210535512 A CN 201210535512A CN 102977039 A CN102977039 A CN 102977039A
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- 239000013078 crystal Substances 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 229960005206 pyrazinamide Drugs 0.000 title abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000002425 crystallisation Methods 0.000 claims abstract description 7
- 230000008025 crystallization Effects 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 239000007787 solid Substances 0.000 claims abstract description 3
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000001291 vacuum drying Methods 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000010521 absorption reaction Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 4
- 238000004090 dissolution Methods 0.000 abstract 1
- 238000001816 cooling Methods 0.000 description 6
- 238000002329 infrared spectrum Methods 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 4
- 206010022000 influenza Diseases 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 2
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229940122277 RNA polymerase inhibitor Drugs 0.000 description 1
- 241000906946 Sphingomonas carri Species 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 235000014666 liquid concentrate Nutrition 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
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Abstract
The invention relates to an alpha crystal form of 6-fluo-3-hydroxyl-2-pyrazinecarboxamide and a preparation method thereof. The alpha crystal form of 6-fluo-hydroxyl-2-pyrazinecarboxamide is white or off-white solid in appearance, has cell parameters as follows: alpha=90 degrees, beta=90 degrees and gamma=90 degrees, and has a spatial structure in lamellar arrangement, wherein molecules are connected through hydrogen bonds. The preparation method comprises the steps of: dissolving 6-fluo-3-hydroxyl-2-pyrazinecarboxamide in a solvent as per (1:5)-(1:20)g/ml, carrying out water-bath heating for dissolution, then, placing into a water bath at 25-40 DEG C, standing, and when crystals begin to separate out, carrying out crystallization at -15-0 DEG C; and filtering and drying in vacuum for 6-8h at 55-65 DEG C. The prepared alpha crystal form of 6-fluo-3-hydroxyl-2-pyrazinecarboxamide has high purity, high yield and stability; and the preparation method is simple in process and easy to implement and has the yield being 90-95% and the purity being not smaller than 99.90%.
Description
Technical field
The invention belongs to drug crystal forms and find and preparing technical field, be specifically related to a kind of T-705 new crystal and preparation method thereof.
Background technology
T-705 is a kind of compound for prevention and treatment disease of viral infection, particularly influenza infection etc.Its structural formula is as follows:
T-705 is as the inhibitor of RNA polymerase, by Fushan Mountain chemistry initiative, because discovery in the research that the U.S. carries out has been brought into play obvious result for the treatment of to the small white mouse that has infected highly pathogenic H5N1 type avian influenza virus, thereby advanced it as the R﹠D work for the treatment of influenza medicine that comprises H5N1 type influenza.The Fushan Mountain chemistry has been implemented the clinical second stage experiment of T-705 since in January, 2008 to the seasonal influenza patient, has confirmed that tentatively the RNA polymerase inhibitor of this new texture also has drug effect for human body; In October, 2009, it is clinical that T-705 enters the III phase; And in March, 2011 application in Japan's listing, in the middle of examining at present.
In WO12043700A1 and WO12043696A1, sodium salt and the hydrate of meglumine salt and the crystal formation of freeze-drying crystal by the T-705 of Toyama Chemical Co., Ltd.'s invention have been put down in writing; In Chinese patent CN102348458A, put down in writing the tablet that contains T-705 and dry liquid concentrate by Toyama Chemical Co., Ltd.'s invention, but do not reported its preparation crystal formation; Therefore the crystal crystal formation of the T-705 just do not reported of the inventor has carried out further research.
Summary of the invention
It is high that the present invention aims to provide a kind of purity, and yield is high, the T-705 crystal formation of stable crystal form, and the method for a kind of technique this drug crystal forms of preparation simple, easy to implement.
Technical scheme of the present invention is: the alpha-crystal form of T-705, its outward appearance are white or off-white color solid, and its unit cell parameters is
α=90 °, β=90 °, γ=90 °, its space structure is layered arrangement, is intermolecularly connected by hydrogen bond.
The preparation method of T-705 alpha-crystal form is:
(1) dissolving: T-705 is dissolved in the solvent, and heating in water bath refluxes and dissolves; The consumption of T-705 and solvent is: T-705: solvent=1:5～1:20g/mL, preferred 1:10～1:15g/mL;
(2) crystallization: dissolving is placed in 25～40 ℃ of water-baths of temperature leaves standstill, and when beginning to have crystal to separate out, is positioned over temperature-15～0 ℃ lower crystallization;
(3) filtration drying: filter, in 55～65 ℃ of lower vacuum-dryings of temperature 6～8 hours;
Described solvent is a kind of in methyl alcohol, ethanol, methylene dichloride, tetrahydrofuran (THF), acetone or the ethyl acetate.
Described crystal shows the X-ray powder diffraction peak at 11.8-11.9 ° of reflection angle 2 θ value, 20.2-20.3 °, 22.8-22.9 ° and 27.8-27.9 °.
Described crystal is at 1264-1266cm
-1, 1397-1399cm
-1, 1437-1441cm
-1, 1670-1673cm
-1, 3224-3227cm
-1And 3347-3356cm
-1Show infrared absorption peak.
Beneficial effect of the present invention is: the T-705 alpha-crystal form purity that makes is high, and yield is high, stable crystal form; Its preparation method technique is simple, easy to implement, and yield is 90%～95%, purity 〉=99.90%.
Description of drawings
Fig. 1 is the space structure synoptic diagram of T-705 alpha-crystal form among the present invention;
Fig. 2 is the infrared absorpting light spectra of T-705 alpha-crystal form among the embodiment 1;
Fig. 3 is the X-ray powder diffraction figure of T-705 alpha-crystal form among the embodiment 1;
Fig. 4 is the infrared absorpting light spectra of T-705 alpha-crystal form among the embodiment 2;
Fig. 5 is the X-ray powder diffraction figure of T-705 alpha-crystal form among the embodiment 2;
Fig. 6 is the infrared absorpting light spectra of T-705 alpha-crystal form among the embodiment 3.
Fig. 7 is the X-ray powder diffraction figure of T-705 alpha-crystal form among the embodiment 3.
Fig. 8 is the infrared absorpting light spectra of T-705 alpha-crystal form among the embodiment 4;
Fig. 9 is the X-ray powder diffraction figure of T-705 alpha-crystal form among the embodiment 4;
Figure 10 is the infrared absorpting light spectra of T-705 alpha-crystal form among the embodiment 5;
Figure 11 is the X-ray powder diffraction figure of T-705 alpha-crystal form among the embodiment 5;
Figure 12 is the infrared absorpting light spectra of T-705 alpha-crystal form among the embodiment 6;
Figure 13 is the X-ray powder diffraction figure of T-705 alpha-crystal form among the embodiment 6.
Embodiment
Specify the present invention below in conjunction with embodiment.
The preparation method is as follows: the 4.0g T-705 is dissolved in the 20ml methyl alcohol, heating in water bath refluxed 10 minutes, after the cooling, place 25 ℃ of waters bath with thermostatic control to leave standstill solution, when beginning to have crystal to separate out, then be positioned over-15 ℃ of lower crystallizatioies, after the filtration, namely got 3.6g6-fluoro-3-hydroxyl-2-Zinamide alpha-crystal form crystal in 7 hours in 60 ℃ of lower vacuum-dryings.
Detect through infrared spectra, see Fig. 2, at 1264.91cm-1,1398.06cm-1,1438.30cm-1,1672.77cm-1,3226.29cm-1 and 3349.75cm-1 place characteristic peak is arranged.
Through X-ray powder diffraction, see Fig. 3, reflection angle 2 θ have located the obvious characteristic peak about 11.87 °, 20.28 °, 22.87 ° and 27.82 °.
The preparation method is as follows: the 4.0g T-705 is dissolved in the 30ml ethanol, heating in water bath refluxed 10 minutes, after the cooling, place 30 ℃ of waters bath with thermostatic control to leave standstill solution, when beginning to have crystal to separate out, then be positioned over-5 ℃ of lower crystallizatioies, after the filtration, namely got 3.8g T-705 alpha-crystal form crystal in 7 hours in 60 ℃ of lower vacuum-dryings.
Detect through infrared spectra, see Fig. 4, at 1264.49cm-1,1397.40cm-1,1437.45cm-1,1671.84cm-1,3225.01cm-1 and 3349.00cm-1 place characteristic peak is arranged.
Through X-ray powder diffraction, see Fig. 5, reflection angle 2 θ have located the obvious characteristic peak about 11.87 °, 20.29 °, 22.87 °, 23.99 °, 27.17 ° and 27.82 °.
Embodiment 3
The preparation method is as follows: the 4.0g T-705 is dissolved in the 80ml methylene dichloride, heating in water bath refluxed 10 minutes, after the cooling, place about 25 ℃ of waters bath with thermostatic control to leave standstill solution, when beginning to have crystal to separate out, then be positioned over 0 ℃ of lower crystallization, after the filtration, namely got 3.7g T-705 alpha-crystal form crystal in 7 hours in 60 ℃ of lower vacuum-dryings.
Detect through infrared spectra, see Fig. 6, at 1264.38cm-1,1397.68cm-1,1440.32cm-1,1670.69cm-1,3226.69cm-1 and 3351.99cm-1 place characteristic peak is arranged.
Through X-ray powder diffraction, see Fig. 7, reflection angle 2 θ have located the obvious characteristic peak about 11.88 °, 19.74 °, 20.28 °, 22.87 °, 23.99 °, 27.16 ° and 27.83 °.
Embodiment 4
The preparation method is as follows: the 4.0g T-705 is dissolved in the 80ml tetrahydrofuran (THF), heating in water bath refluxed 10 minutes, after the cooling, place about 40 ℃ of waters bath with thermostatic control to leave standstill solution, when beginning to have crystal to separate out, then be positioned over 0 ℃ of lower crystallization, after the filtration, namely got 3.6g6-fluoro-3-hydroxyl-2-Zinamide alpha-crystal form crystal in 7 hours in 60 ℃ of lower vacuum-dryings.
Detect through infrared spectra, see Fig. 8, at 1264.52cm-1,1397.21cm-1,1437.49cm-1,1672.38cm-1,3224.41cm-1 and 3350.74cm-1 place characteristic peak is arranged.
Through X-ray powder diffraction, see Fig. 9, reflection angle 2 θ have located the obvious characteristic peak about 11.90 °, 19.75 °, 20.31 °, 22.87 °, 24.01 °, 27.18 ° and 27.86 °.
Embodiment 5
The preparation method is as follows: the 4.0g T-705 is dissolved in the 50ml acetone, heating in water bath refluxed 10 minutes, after the cooling, place about 25 ℃ of waters bath with thermostatic control to leave standstill solution, when beginning to have crystal to separate out, then be positioned over-15 ℃ of lower crystallizatioies, after the filtration, namely got 3.6g6-fluoro-3-hydroxyl-2-Zinamide alpha-crystal form crystal in 7 hours in 60 ℃ of lower vacuum-dryings.
Detect through infrared spectra, see Figure 10, at 1265.02cm-1,1398.17cm-1,1438.06cm-1,1673.29cm-1,3226.41cm-1 and 3347.66cm-1 place characteristic peak is arranged.
Through X-ray powder diffraction, see Figure 11, reflection angle 2 θ have located the obvious characteristic peak about 11.89 °, 19.74 °, 20.28 °, 22.87 °, 23.97 °, 27.16 ° and 27.86 °.
Embodiment 6
The preparation method is as follows: the 4.0g T-705 is dissolved in the 50ml ethyl acetate, heating in water bath refluxed 10 minutes, after the cooling, place about 25 ℃ of waters bath with thermostatic control to leave standstill solution, when beginning to have crystal to separate out, then be positioned over-15 ℃ of lower crystallizatioies, after the filtration, namely got 3.6g6-fluoro-3-hydroxyl-2-Zinamide alpha-crystal form crystal in 7 hours in 60 ℃ of lower vacuum-dryings.
Detect through infrared spectra, see Figure 12, at 1265.42cm-1,1397.93cm-1,1438.17cm-1,1672.05cm-1,3228.31cm-1 and 3352.71cm-1 place characteristic peak is arranged.
Through X-ray powder diffraction, see Figure 13, reflection angle 2 θ have located the obvious characteristic peak about 11.85 °, 19.74 °, 20.26 °, 22.87 °, 23.99 °, 27.15 ° and 27.86 °.
Claims (5)
1. the alpha-crystal form of a T-705 is characterized in that, its outward appearance is white or off-white color solid, and its unit cell parameters is
α=90 °, β=90 °, γ=90 °, its space structure is layered arrangement, is intermolecularly connected by hydrogen bond.
2. the alpha-crystal form of T-705 according to claim 1 is characterized in that, reflection angle 2 θ of its X-ray powder diffraction figure are about 11.8-11.9 °, 20.2-20.3 °, 22.8-22.9 ° and 27.8-27.9 °.
3. the alpha-crystal form of T-705 according to claim 1 is characterized in that, it is at 1264-1266cm
-1, 1397-1399cm
-1, 1437-1441cm
-1, 1670-1673cm
-1, 3224-3227cm
-1And 3347-3356cm
-1Show infrared absorption peak.
4. the alpha-crystal form of the described T-705 of each claim according to claim 1-3, its preparation method is:
(1) dissolving: T-705 is dissolved in the solvent, and heating in water bath refluxes and dissolves; The consumption of T-705 and solvent is: T-705: solvent=1:5～1:20g/mL;
(2) crystallization: dissolving is placed in 25～40 ℃ of water-baths of temperature leaves standstill, and when beginning to have crystal to separate out, is positioned over temperature-15～0 ℃ lower crystallization;
(3) filtration drying: filter, in 55～65 ℃ of lower vacuum-dryings of temperature 6～8 hours;
Described solvent is a kind of in methyl alcohol, ethanol, methylene dichloride, tetrahydrofuran (THF), acetone or the ethyl acetate.
5. the preparation method of the alpha-crystal form of T-705 according to claim 4, it is characterized in that the consumption of described T-705 and solvent is: T-705: solvent=solvent=1:10～1:15g/mL.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111875550A (en) * | 2020-07-24 | 2020-11-03 | 内蒙古京东药业有限公司 | Crystal form of Favipiravir dimethyl sulfoxide solvate and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102348458A (en) * | 2009-03-13 | 2012-02-08 | 富山化学工业株式会社 | Tablet and granulated powder containing 6-fluoro-3-hydroxy-2-pyrazinecarboxamide |
| CN102775358A (en) * | 2012-08-22 | 2012-11-14 | 山东齐都药业有限公司 | Preparation method of 6-fluoro-3-hydroxy-2-pyrazinamide |
-
2012
- 2012-12-12 CN CN201210535512.9A patent/CN102977039B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102348458A (en) * | 2009-03-13 | 2012-02-08 | 富山化学工业株式会社 | Tablet and granulated powder containing 6-fluoro-3-hydroxy-2-pyrazinecarboxamide |
| CN102775358A (en) * | 2012-08-22 | 2012-11-14 | 山东齐都药业有限公司 | Preparation method of 6-fluoro-3-hydroxy-2-pyrazinamide |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111875550A (en) * | 2020-07-24 | 2020-11-03 | 内蒙古京东药业有限公司 | Crystal form of Favipiravir dimethyl sulfoxide solvate and preparation method thereof |
| CN111875550B (en) * | 2020-07-24 | 2023-06-06 | 内蒙古京东药业有限公司 | Crystal form of fampicin dimethyl sulfoxide solvate and preparation method thereof |
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Inventor after: Zhang Tao Inventor after: Kong Lingjin Inventor after: Dong Xu Inventor after: Li Zongtao Inventor after: Niu Haigang Inventor after: Liu Jie Inventor after: Jiang Juan Inventor before: Kong Lingjin Inventor before: Zhang Tao Inventor before: Li Zongtao Inventor before: Niu Haigang |
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Denomination of invention: 6-fluoro-3-hydroxy-2-pyrazine formamide a Crystal form and preparation method thereof Effective date of registration: 20211202 Granted publication date: 20140910 Pledgee: CITIC Bank Limited by Share Ltd. Zibo branch Pledgor: SHANDONG QIDU PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980013861 |
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Date of cancellation: 20220719 Granted publication date: 20140910 Pledgee: CITIC Bank Limited by Share Ltd. Zibo branch Pledgor: SHANDONG QIDU PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980013861 |
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