CN102977039B - 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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- CN102977039B CN102977039B CN201210535512.9A CN201210535512A CN102977039B CN 102977039 B CN102977039 B CN 102977039B CN 201210535512 A CN201210535512 A CN 201210535512A CN 102977039 B CN102977039 B CN 102977039B
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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
- 238000002425 crystallisation Methods 0.000 claims abstract description 11
- 230000008025 crystallization Effects 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 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
- 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
- ZCGNOVWYSGBHAU-UHFFFAOYSA-N favipiravir Chemical class NC(=O)C1=NC(F)=CNC1=O ZCGNOVWYSGBHAU-UHFFFAOYSA-N 0.000 claims description 48
- 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
- 238000010992 reflux Methods 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
- 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
- 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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
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 for preventing and treat the compound of 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, in the research that the Yin U.S. carries out, find to have brought into play obvious result for the treatment of to having infected the small white mouse of highly pathogenic H5N1 type avian influenza virus, thereby advanced using it as the R&D work for comprising the treatment of influenza medicine of H5N1 type influenza.Fushan Mountain chemistry has been implemented the clinical second stage experiment of T-705 since in January, 2008 to seasonal influenza patient, has tentatively confirmed that 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 application is gone on the market in Japan in March, 2011, in the middle of examining at present.
In WO12043700A1 and WO12043696A1, record the sodium salt of T-705 of Liao You Toyama Chemical Co., Ltd. invention and the crystal formation of the hydrate of meglumine salt and freeze-drying crystal thereof; In Chinese patent CN102348458A, record the tablet that contains T-705 and the dry liquid concentrate of the invention of Liao You Toyama Chemical Co., Ltd., but do not report its preparation crystal formation; The crystal crystal formation of the T-705 that therefore inventor does not just report has carried out further research.
Summary of the invention
The present invention aims to provide that a kind of purity is high, 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, and its outward appearance is white or off-white color solid, its unit cell parameters is
α=90 °, β=90 °, γ=90 °, its space structure is layered arrangement, intermolecularly by hydrogen bond, is connected.
The preparation method of T-705 alpha-crystal form is:
(1) dissolve: T-705 is dissolved in 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, preferably 1:10～1:15g/mL;
(2) crystallization: dissolve and to be placed in 25～40 ℃ of water-baths of temperature standingly, when starting to have crystal to separate out, be positioned over crystallization at temperature-15～0 ℃;
(3) filtration drying: filter, vacuum-drying is 6～8 hours at 55～65 ℃ of temperature;
Described solvent is a kind of in methyl alcohol, ethanol, methylene dichloride, tetrahydrofuran (THF), acetone or ethyl acetate.
Described crystal shows 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 making 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%.
Accompanying drawing explanation
Fig. 1 is the space structure schematic diagram of T-705 alpha-crystal form in the present invention;
Fig. 2 is the infrared absorpting light spectra of T-705 alpha-crystal form in embodiment 1;
Fig. 3 is the X-ray powder diffraction figure of T-705 alpha-crystal form in embodiment 1;
Fig. 4 is the infrared absorpting light spectra of T-705 alpha-crystal form in embodiment 2;
Fig. 5 is the X-ray powder diffraction figure of T-705 alpha-crystal form in embodiment 2;
Fig. 6 is the infrared absorpting light spectra of T-705 alpha-crystal form in embodiment 3.
Fig. 7 is the X-ray powder diffraction figure of T-705 alpha-crystal form in embodiment 3.
Fig. 8 is the infrared absorpting light spectra of T-705 alpha-crystal form in embodiment 4;
Fig. 9 is the X-ray powder diffraction figure of T-705 alpha-crystal form in embodiment 4;
Figure 10 is the infrared absorpting light spectra of T-705 alpha-crystal form in embodiment 5;
Figure 11 is the X-ray powder diffraction figure of T-705 alpha-crystal form in embodiment 5;
Figure 12 is the infrared absorpting light spectra of T-705 alpha-crystal form in embodiment 6;
Figure 13 is the X-ray powder diffraction figure of T-705 alpha-crystal form in embodiment 6.
Embodiment
Below in conjunction with embodiment, illustrate the present invention.
Embodiment 1
Preparation method is as follows: 4.0g T-705 is dissolved in 20ml methyl alcohol, heating in water bath refluxes 10 minutes, after cooling, solution is placed in to 25 ℃ of waters bath with thermostatic control standing, when starting to have crystal to separate out, then be positioned over crystallization at-15 ℃, after filtration, at 60 ℃, vacuum-drying obtain the fluoro-3-hydroxyl-2-of 3.6g6-Zinamide alpha-crystal form crystal for 7 hours.
Through infrared spectra, detect, see Fig. 2, at 1264.91cm-1,1398.06cm-1,1438.30cm-1,1672.77cm-1,3226.29cm-1 and 3349.75cm-1 place, have characteristic peak.
Through X-ray powder diffraction, see Fig. 3, reflection angle 2 θ have located obvious characteristic peak about 11.87 °, 20.28 °, 22.87 ° and 27.82 °.
Embodiment 2
Preparation method is as follows: 4.0g T-705 is dissolved in 30ml ethanol, heating in water bath refluxes 10 minutes, after cooling, solution is placed in to 30 ℃ of waters bath with thermostatic control standing, when starting to have crystal to separate out, then be positioned over crystallization at-5 ℃, after filtration, at 60 ℃, vacuum-drying obtain 3.8g T-705 alpha-crystal form crystal for 7 hours.
Through infrared spectra, detect, see Fig. 4, at 1264.49cm-1,1397.40cm-1,1437.45cm-1,1671.84cm-1,3225.01cm-1 and 3349.00cm-1 place, have characteristic peak.
Through X-ray powder diffraction, see Fig. 5, reflection angle 2 θ have located obvious characteristic peak about 11.87 °, 20.29 °, 22.87 °, 23.99 °, 27.17 ° and 27.82 °.
Embodiment 3
Preparation method is as follows: 4.0g T-705 is dissolved in 80ml methylene dichloride, heating in water bath refluxes 10 minutes, after cooling, solution is placed in to approximately 25 ℃ of waters bath with thermostatic control standing, when starting to have crystal to separate out, then be positioned over crystallization at 0 ℃, after filtration, at 60 ℃, vacuum-drying obtain 3.7g T-705 alpha-crystal form crystal for 7 hours.
Through infrared spectra, detect, see Fig. 6, at 1264.38cm-1,1397.68cm-1,1440.32cm-1,1670.69cm-1,3226.69cm-1 and 3351.99cm-1 place, have characteristic peak.
Through X-ray powder diffraction, see Fig. 7, reflection angle 2 θ have located obvious characteristic peak about 11.88 °, 19.74 °, 20.28 °, 22.87 °, 23.99 °, 27.16 ° and 27.83 °.
Embodiment 4
Preparation method is as follows: 4.0g T-705 is dissolved in 80ml tetrahydrofuran (THF), heating in water bath refluxes 10 minutes, after cooling, solution is placed in to approximately 40 ℃ of waters bath with thermostatic control standing, when starting to have crystal to separate out, then be positioned over crystallization at 0 ℃, after filtration, at 60 ℃, vacuum-drying obtain the fluoro-3-hydroxyl-2-of 3.6g6-Zinamide alpha-crystal form crystal for 7 hours.
Through infrared spectra, detect, see Fig. 8, at 1264.52cm-1,1397.21cm-1,1437.49cm-1,1672.38cm-1,3224.41cm-1 and 3350.74cm-1 place, have characteristic peak.
Through X-ray powder diffraction, see Fig. 9, reflection angle 2 θ have located obvious characteristic peak about 11.90 °, 19.75 °, 20.31 °, 22.87 °, 24.01 °, 27.18 ° and 27.86 °.
Embodiment 5
Preparation method is as follows: 4.0g T-705 is dissolved in 50ml acetone, heating in water bath refluxes 10 minutes, after cooling, solution is placed in to approximately 25 ℃ of waters bath with thermostatic control standing, when starting to have crystal to separate out, then be positioned over crystallization at-15 ℃, after filtration, at 60 ℃, vacuum-drying obtain the fluoro-3-hydroxyl-2-of 3.6g6-Zinamide alpha-crystal form crystal for 7 hours.
Through infrared spectra, detect, see Figure 10, at 1265.02cm-1,1398.17cm-1,1438.06cm-1,1673.29cm-1,3226.41cm-1 and 3347.66cm-1 place, have characteristic peak.
Through X-ray powder diffraction, see Figure 11, reflection angle 2 θ have located obvious characteristic peak about 11.89 °, 19.74 °, 20.28 °, 22.87 °, 23.97 °, 27.16 ° and 27.86 °.
Embodiment 6
Preparation method is as follows: 4.0g T-705 is dissolved in 50ml ethyl acetate, heating in water bath refluxes 10 minutes, after cooling, solution is placed in to approximately 25 ℃ of waters bath with thermostatic control standing, when starting to have crystal to separate out, then be positioned over crystallization at-15 ℃, after filtration, at 60 ℃, vacuum-drying obtain the fluoro-3-hydroxyl-2-of 3.6g6-Zinamide alpha-crystal form crystal for 7 hours.
Through infrared spectra, detect, see Figure 12, at 1265.42cm-1,1397.93cm-1,1438.17cm-1,1672.05cm-1,3228.31cm-1 and 3352.71cm-1 place, have characteristic peak.
Through X-ray powder diffraction, see Figure 13, reflection angle 2 θ have located 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, it is characterized in that, its outward appearance is white or off-white color solid, and its unit cell parameters is a=9.1106 (8) A, b=14.7619 (14) A, c=4.6910 (4) A, α=90 °, β=90 °, γ=90 °, its space structure is layered arrangement, intermolecularly by hydrogen bond, is connected.
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 at 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. according to the alpha-crystal form of the T-705 described in any one claim in claim 1-3, its preparation method is:
Dissolve: T-705 is dissolved in 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;
Crystallization: dissolve and to be placed in 25～40 ℃ of water-baths of temperature standingly, when starting to have crystal to separate out, be positioned over crystallization at temperature-15～0 ℃;
Filtration drying: filter, vacuum-drying is 6～8 hours at 55～65 ℃ of temperature;
Described solvent is a kind of in methyl alcohol, ethanol, methylene dichloride, tetrahydrofuran (THF), acetone or 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=1:10～1:15g/mL.
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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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Free format text: CORRECT: INVENTOR; FROM: KONG LINGJIN ZHANG TAO LI ZONGTAO NIU HAIGANG TO: ZHANG TAO KONG LINGJIN DONG XU LI ZONGTAO NIU HAIGANG LIU JIE JIANG JUAN |
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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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