CN109134566A - A kind of 1/20 water Ribavirin compound - Google Patents
A kind of 1/20 water Ribavirin compound Download PDFInfo
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- CN109134566A CN109134566A CN201710709626.3A CN201710709626A CN109134566A CN 109134566 A CN109134566 A CN 109134566A CN 201710709626 A CN201710709626 A CN 201710709626A CN 109134566 A CN109134566 A CN 109134566A
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- Prior art keywords
- water
- ribavirin
- compound
- ribavirin compound
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- 229960000329 ribavirin Drugs 0.000 title claims abstract description 68
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 title claims abstract description 68
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 58
- -1 Ribavirin compound Chemical class 0.000 title claims abstract description 44
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract description 33
- 238000002425 crystallisation Methods 0.000 abstract description 14
- 230000008025 crystallization Effects 0.000 abstract description 14
- 239000012043 crude product Substances 0.000 abstract description 6
- 239000000047 product Substances 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 238000000034 method Methods 0.000 description 26
- 230000000052 comparative effect Effects 0.000 description 22
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 229910052760 oxygen Inorganic materials 0.000 description 10
- 230000006837 decompression Effects 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 238000002411 thermogravimetry Methods 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 4
- 238000004566 IR spectroscopy Methods 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 3
- 229940017687 beta-d-ribose Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 3
- 235000019799 monosodium phosphate Nutrition 0.000 description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- ZEWJFUNFEABPGL-UHFFFAOYSA-N 1,2,4-triazole-3-carboxamide Chemical compound NC(=O)C=1N=CNN=1 ZEWJFUNFEABPGL-UHFFFAOYSA-N 0.000 description 2
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229930010555 Inosine Natural products 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229940029575 guanosine Drugs 0.000 description 2
- 229960003786 inosine Drugs 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 239000012495 reaction gas Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 1
- OQRXBXNATIHDQO-UHFFFAOYSA-N 6-chloropyridine-3,4-diamine Chemical compound NC1=CN=C(Cl)C=C1N OQRXBXNATIHDQO-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229940124186 Dehydrogenase inhibitor Drugs 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- UBORTCNDUKBEOP-UHFFFAOYSA-N L-xanthosine Natural products OC1C(O)C(CO)OC1N1C(NC(=O)NC2=O)=C2N=C1 UBORTCNDUKBEOP-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010035737 Pneumonia viral Diseases 0.000 description 1
- 101710101148 Probable 6-oxopurine nucleoside phosphorylase Proteins 0.000 description 1
- 102100036286 Purine nucleoside phosphorylase Human genes 0.000 description 1
- 102000030764 Purine-nucleoside phosphorylase Human genes 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- UBORTCNDUKBEOP-HAVMAKPUSA-N Xanthosine Natural products O[C@@H]1[C@H](O)[C@H](CO)O[C@H]1N1C(NC(=O)NC2=O)=C2N=C1 UBORTCNDUKBEOP-HAVMAKPUSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- YXJDFQJKERBOBM-TXICZTDVSA-N alpha-D-ribose 1-phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(O)=O)[C@H](O)[C@@H]1O YXJDFQJKERBOBM-TXICZTDVSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 208000002352 blister Diseases 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005262 decarbonization Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- 108010009099 nucleoside phosphorylase Proteins 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 208000009421 viral pneumonia Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- UBORTCNDUKBEOP-UUOKFMHZSA-N xanthosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(NC(=O)NC2=O)=C2N=C1 UBORTCNDUKBEOP-UUOKFMHZSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/056—Triazole or tetrazole radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of 1/20 water Ribavirin compound, every mole of Ribavirin compound contains 1/20 mole of water.The present invention by by Ribavirin crude product it is soluble in water after, control solution temperature and pH value, 1/20 water Ribavirin compound is made in the crystallization in aqueous acetonitrile agent.Product purity produced by the present invention is high, and stability is good, has and value is applied even more extensively.
Description
Technical field
The invention belongs to chemical engineering medicine crystallization technique fields, are related to 1/20 water Ribavirin compound of one kind and its system
Method.
Background technique
Ribavirin is a kind of non-selective ucleosides broad-spectrum antiviral drug, belongs to monophosphate inosine (IMP)
Dehydrogenase inhibitor participates in guanine metabolism in human body, interferes the biosynthesis of guanine, the duplication of virus prevented, to more
Kind DNA and RNA virus have inhibiting effect.Viral pneumonia caused by clinical treatment Respiratory Syncytial Virus(RSV) and bronchus
Inflammation, influenza, encephalitis, varicella, rubeola, bleb etc..
There are three types of methods for the synthesis of Ribavirin: chemical method, fermentation method, enzymatic method
Chemical method is such as: CN 101891786A is condensed by 1,2,3,5-Tetra-O-Acetyl-D-Ribose and triazole methyl esters, then benefit bar is made in ammonolysis
Wei Lin.
Fermentation method is such as: CN 105483189A is to be overexpressed the genetic engineering bacterium BL21/Pet- of purine nucleoside phosphorylase
His-pupG is production bacterial strain, using lactose Fiber differentiation cell, in phosphate buffer, catalysis substrate guanosine and 1,2,4-
Triazole -3- formamide prepares Ribavirin.
For enzymatic method with inosine, guanosine, xanthosine or D-ribose -1- phosphate and 1,2,4- triazole -3- carboxylic acid amides are raw material,
Ribavirin is synthesized under the action of nucleoside phosphorylase esterase.
The Ribavirin of above-mentioned three kinds of methods preparation, haves the shortcomings that purity difference and stability are poor, the present inventor is
A kind of purity is high, stability is made by carrying out numerous studies to the factor for influencing its crystallization in the stabilization for improving Ribavirin
Good Ribavirin compound.
Summary of the invention
The invention discloses the new solvates of one kind of Ribavirin, are more specifically 1/20 water Ribavirin chemical combination
Object, i.e. every mole of Ribavirin compound contain 1/20 mole of water, molecular formula C8H12N4O51/20H2O, and molecular weight is
245.11 structural formula is as follows:
1/20 water Ribavirin compound of the present invention, preparation the following steps are included:
It adds water in container, controls temperature, Ribavirin crude product, stirring and dissolving, with disodium hydrogen phosphate and phosphorus is added
Acid dihydride sodium controls pH value, adds active carbon, stirring and adsorbing decoloration, and decompression filters, and is rinsed with water filter cake, takes filtrate to be added anti-
It answers in kettle, reduces temperature, be slowly added to acetonitrile, stand crystallization, decompression filters, and filter cake is washed with acetonitrile, is dried under reduced pressure, and obtains 1/20
Water Ribavirin compound.
Preferably, described controlled at 40~70 DEG C in above-mentioned preparation method, it is highly preferred that controlled at 50~
60℃。
Preferably, in above-mentioned preparation method, the control pH value is 4~7, it is highly preferred that control pH value is 5~6.
Preferably, in above-mentioned preparation method, the crystallization temperature is 0~30 DEG C, it is highly preferred that crystallization temperature is 10~20
℃。
Preferably, in above-mentioned preparation method, the crystallization time is 1~5h, it is highly preferred that the crystallization time is 2~4h.
Preferably, in above-mentioned preparation method, the drying temperature be 30~70 DEG C, it is highly preferred that drying temperature be 40~
60℃。
Preferably, in above-mentioned preparation method, the drying time is 0.5~3h, it is highly preferred that drying temperature is 1~2h.
Karl_Fischer method is that one of the most single-minded, accurate method, the present invention are public in moisture method in various measurement substances
Between 0.32~0.43%, theoretical water content is the Ribavirin compound Karl_Fischer method measurement moisture content opened
0.37%, it may be determined that each Ribavirin compound of the present invention contains 1/20 mole of water.
1/20 water Ribavirin compound of the present invention, TG are analyzed the results show that weightlessness about 0.34%, Li Bawei
The theoretical percentage composition of water is 0.37% in standing forest, referring to expense Xiu Shi method measure Ribavirin moisture content be 0.32~
0.43%, and it is 0.34% that experiment, which measures TG weightlessness, is consistent substantially with theoretical water content.It can be inferred that Ribavirin TG is weightless
It is caused by removing water, and every mole of Ribavirin contains 1/20 mole of water.As shown in Fig. 1.Data are by heat analysis-mass spectrometer
(NETZSCH STA 449C) analysis obtains.Analysis condition are as follows: 2~10mg of sample, alumina crucible, high pure nitrogen do reaction gas
With protection gas, flow is respectively 40ml/min and 30ml/min, and heating rate 10K/min, temperature test range is 25~400
℃.Sample decomposition temperature is about 254.9 DEG C.
1/20 water Ribavirin compound of the present invention, infrared spectroscopy are 3451.7 ± 2cm in wave number-1,
3349.1±2cm-1, 2955.6 ± 2cm-1, 1663.3 ± 2cm-1, 1502.8 ± 2cm-1, 1438.4 ± 2cm-1, 1362.1 ±
2cm-1, 1234.6 ± 2cm-1, 1070.6 ± 2cm-1, 958.7 ± 2cm-1, 836.6 ± 2cm-1, 773.2 ± 2cm-1There is feature at place
Absorption peak, as shown in Fig. 2.Examination of infrared spectrum condition are as follows: Agilent Cary 630, pressing potassium bromide troche.
1/20 water Ribavirin compound of the present invention, x-ray diffractogram of powder spectrum are 11.97 in 2 θ of the angle of diffraction
± 0.2 °, 13.45 ± 0.2 °, 18.22 ± 0.2 °, 23.30 ± 0.2 °, 24.11 ± 0.2 °, 25.40 ± 0.2 °, 27.12 ±
There is characteristic diffraction peak at 0.2 °, 29.18 ± 0.2 °, the opposite diffracted intensity of the angle of diffraction is respectively 100,48.66,21.72,
60.30,76.51,67.64,47.33,50.94.As shown in Fig. 3.X-ray powder diffraction test condition: Holland
EMPYREAN (sharp shadow) X-ray diffractometer of Panalytical company, CuK α radiation, light pipe voltage 40kV, heater current
300mA, continuous scanning, 0.02 ° of step-length, 8 °/min of scanning speed, scanning range is 2~50 °.
1/20 water Ribavirin compound of the present invention, dsc analysis is the results show that have heat absorption at about 172.0 DEG C
There is exothermic peak at peak at about 270.8 DEG C.As shown in Fig. 4.DSC data is by heat analysis-mass spectrometer (NETZSCH STA
449C) analysis obtains, analysis condition are as follows: 2~10mg of sample, alumina crucible, high pure nitrogen do reaction gas and protection gas, flow
Respectively 40ml/min and 30ml/min.10 DEG C/min of heating rate, 25~400 DEG C of temperature range.
Further purpose of the invention provides a kind of pharmaceutical composition containing 1/20 water Ribavirin compound.It is excellent
Selection of land, described pharmaceutical composition include 1/20 water Ribavirin compound and the excipient pharmaceutically received.It is highly preferred that drug
Composition is selected from pharmaceutically acceptable dosage form.
Detailed description of the invention
The TG analysis chart of 1/20 water Ribavirin compound of Fig. 1.
The FTIR spectrum figure of 1/20 water Ribavirin compound of Fig. 2.
The x-ray diffractogram of powder of 1/20 water Ribavirin compound of Fig. 3 is composed.
The dsc analysis figure of 1/20 water Ribavirin compound of Fig. 4.
Specific embodiment
Below will by specific embodiment, the present invention will be further described, but therefore do not limit the present invention to institute
In the scope of embodiments stated, it should be understood by those skilled in the art that changing to the equivalent replacement that the content of present invention is done, or accordingly
Into still falling within protection scope of the present invention.
The preparation of embodiment 1:1/20 water Ribavirin compound
1000ml water is added in container, temperature is controlled at 50 DEG C, 100.06g Ribavirin crude product is added, stir molten
Solution adds 1.02g active carbon with disodium hydrogen phosphate and sodium dihydrogen phosphate control pH value 5.0, and stirring and adsorbing is decolourized 30min,
Decompression filters, and rinses filter cake with 50ml water, filtrate is taken to be added in reaction kettle, reduces temperature to 15 DEG C, is slowly added to acetonitrile
1000ml stands crystallization 2h, and decompression filters, and filter cake is washed with acetonitrile 50ml, and 40 DEG C are dried under reduced pressure 2h, obtain 1/20 water Ribavirin
Compound 92.62g.
As a result:
X-ray diffractogram of powder spectrum 2 θ of the angle of diffraction be 11.97 °, 13.45 °, 18.22 °, 23.30 °, 24.11 °,
There is characteristic diffraction peak at 25.40 °, 27.12 °, 29.18 °, the opposite diffracted intensity of the angle of diffraction is respectively 100,48.66,21.72,
60.30,76.51,67.64,47.33,50.94.
Infrared spectroscopy is 3451.7cm in wave number-1, 3349.1cm-1, 2955.6cm-1, 1663.3cm-1, 1502.8cm-1,
1438.4cm-1, 1362.1cm-1, 1234.6cm-1, 1070.6cm-1, 958.7cm-1, 836.6cm-1, 773.2cm-1There is feature at place
Absorption peak.
It is 99.86% that HPLC method, which detects purity,;It is 0.38% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
0.34%, it is almost the same with the result (theoretical value 0.37%) of 1/20 water contained in this way;Elemental Analysis theory are as follows: C:
39.20%, H:4.98%, N:22.86%, O:32.96%;Measured value are as follows: C:39.18%, H:4.96%, N:22.89%, O:
32.97%.
The preparation of embodiment 2:1/20 water Ribavirin compound
1000ml water is added in container, temperature is controlled at 55 DEG C, 100.14g Ribavirin crude product is added, stir molten
Solution adds 1.05g active carbon with disodium hydrogen phosphate and sodium dihydrogen phosphate control pH value 6.0, and stirring and adsorbing is decolourized 30min,
Decompression filters, and rinses filter cake with 50ml water, filtrate is taken to be added in reaction kettle, reduces temperature to 10 DEG C, is slowly added to acetonitrile
1000ml stands crystallization 4h, and decompression filters, and filter cake is washed with acetonitrile 50ml, and 50 DEG C are dried under reduced pressure 1.5h, obtain 1/20 water conservancy Ba Wei
Woods compound 93.35g.
As a result:
X-ray diffractogram of powder spectrum 2 θ of the angle of diffraction be 11.94 °, 13.46 °, 18.25 °, 23.32 °, 24.12 °,
There is characteristic diffraction peak at 25.43 °, 27.14 °, 29.19 °, the opposite diffracted intensity of the angle of diffraction is respectively 100,47.23,20.85,
61.54,77.19,65.46,46.07,51.25.
Infrared spectroscopy is 3451.3cm in wave number-1, 3349.0cm-1, 2955.8cm-1, 1663.5cm-1, 1502.6cm-1,
1438.9cm-1, 1362.0cm-1, 1234.2cm-1, 1070.4cm-1, 958.8cm-1, 836.5cm-1, 773.4cm-1There is feature at place
Absorption peak.
It is 99.82% that HPLC method, which detects purity,;It is 0.32% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
0.33%, it is almost the same with the result (theoretical value 0.37%) of 1/20 water contained in this way;Elemental Analysis theory are as follows: C:
39.20%, H:4.98%, N:22.86%, O:32.96%;Measured value are as follows: C:39.19%, H:4.98%, N:22.88%, O:
32.95%.
The preparation of embodiment 3:1/20 water Ribavirin compound
1000ml water is added in container, temperature is controlled at 60 DEG C, 100.02g Ribavirin crude product is added, stir molten
Solution adds 1.01g active carbon with disodium hydrogen phosphate and sodium dihydrogen phosphate control pH value 5.5, and stirring and adsorbing is decolourized 30min,
Decompression filters, and rinses filter cake with 50ml water, filtrate is taken to be added in reaction kettle, reduces temperature to 20 DEG C, is slowly added to acetonitrile
1000ml stands crystallization 3h, and decompression filters, and filter cake is washed with acetonitrile 50ml, and 60 DEG C are dried under reduced pressure 1h, obtain 1/20 water Ribavirin
Compound 91.82g.
As a result:
X-ray diffractogram of powder spectrum 2 θ of the angle of diffraction be 11.94 °, 13.44 °, 18.21 °, 23.32 °, 24.12 °,
There is characteristic diffraction peak at 25.44 °, 27.15 °, 29.17 °, the opposite diffracted intensity of the angle of diffraction is respectively 100,49.24,22.75,
58.68,73.70,65.45,46.12,48.77.
Infrared spectroscopy is 3451.8cm in wave number-1, 3349.3cm-1, 2955.8cm-1, 1663.5cm-1, 1502.7cm-1,
1438.2cm-1, 1362.4cm-1, 1234.5cm-1, 1070.6cm-1, 958.8cm-1, 836.3cm-1, 773.0cm-1There is feature at place
Absorption peak.
It is 99.83% that HPLC method, which detects purity,;It is 0.43% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
0.40%, it is almost the same with the result (theoretical value 0.37%) of 1/20 water contained in this way;Elemental Analysis theory are as follows: C:
39.20%, H:4.98%, N:22.86%, O:32.96%;Measured value are as follows: C:39.20%, H:4.96%, N:22.85%, O:
32.99%.
Comparative example 1 prepares Ribavirin compound according to existing technical literature CN 101891786A
Using the patent Example 1 and the identical method of embodiment 2
Preparation method:
1- (2,3,5- tri- -0- acetyl group-β-D-RIBOSE base) -1H-1, the synthesis of 2,4- triazole -3- carboxylate methyl esters
In the there-necked flask equipped with thermometer and churned mechanically 2000ml, 318.03g (1mol) 1,2,3,5-Tetra-O-Acetyl-D-Ribose is added,
The triazole methyl esters of 127.10g (1mol), 20.06g trifluoromethanesulfonic acid are put into microwave reactor, and power 400W, heating is arranged
To 55 DEG C, insulation reaction 60min is cooled to room temperature, and 1000ml methanol is added, and is dissolved by heating, is poured out, and is precipitated after cooling a large amount of white
Color solid filters, and washs, dry, obtains 1- (2,3,5- tri- -0- acetyl group-β-D-RIBOSE base) -1H-1,2,4- triazole -3-
Carboxylate methyl ester 346.92g.
The synthesis of Ribavirin
1- (2,3, the 5- tri- -0- acetyl group-β-D-RIBOSE of 191.05g (0.5mol) are added in a high pressure reaction kettle
Base) -1H-1, the methanol of 2,4- triazole -3- carboxylate methyl esters and 2000ml, being passed through nitrogen at room temperature makes reaction kettle keep 2kg's
Pressure reacts 5h, then recycles extra ammonia, and solvent is removed under reduced pressure, and residue ethyl alcohol recrystallization obtains Ribavirin production
Product 107.52g
It is 99.63% that HPLC method, which detects purity,;It is 0.22% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
0.23%;Elemental Analysis theory are as follows: C:39.35%, H:4.95%, N:22.94%, O:32.76%;Measured value are as follows: C:
39.38%, H:4.94%, N:22.92%, O:32.76%.
Comparative example 2 prepares Ribavirin compound according to existing technical literature CN 102127134A
Using the identical method of patent Example 2
Preparation method:
(1) 100.03g Ribavirin crude product is dissolved in 2000ml purified water, is slowly added to 10% benzoic acid solution, stirs
Reaction is mixed, precipitating is generated, Ribavirin benzoate solid is obtained by filtration.
(2) Ribavirin benzoate solid is dissolved in the mixing of acetonitrile and methylene chloride that 2000ml volume ratio is 2:3
In solvent, 3.00g active carbon, 60 DEG C of stirring 20min is added, filtering decarbonization collects filtrate.
(3) it is for the acetonitrile of 2:3 and the mixed solvent of methylene chloride with volume ratio by chromatography column separating purification by filtrate
Mobile phase, fixed phase stuffing are silica gel, and flow velocity 4.5ml/min, collects filtrate by 30 DEG C of column temperature.
(4) 8% sodium bicarbonate solution is added into filtrate, solid is gradually precipitated, then keeps the temperature and sufficiently stir in 60 DEG C of decompression stirrings
Reaction 2h is mixed, filtering, water washing, 60 DEG C are dried under reduced pressure, and obtain Ribavirin 90.16g.
It is 99.29% that HPLC method, which detects purity,;It is 0.25% that Karl_Fischer method, which measures moisture, and thermogravimetric analysis weightlessness is
0.27%;Elemental Analysis theory are as follows: C:39.35%, H:4.95%, N:22.94%, O:32.76%;Measured value are as follows: C:
39.35%, H:4.93%, N:22.92%, O:32.80%.
1 study on the stability of test example
The Ribavirin compound that the present inventor prepares embodiment 1, comparative example 1, comparative example 2 has carried out stability and has examined
It examines.Temperature is 40 DEG C ± 2 DEG C, is placed 6 months, is sampled respectively at 0,1,2,3,6 the end of month.Inspection target be character, solution it is clear
Clear degree and color, moisture, content and related substance.
As a result: can be seen that by accelerated test result, significant change, comparative example 1 do not occur for the moisture of the embodiment of the present invention 1
It is substantially reduced with the moisture of comparative example 2, can further infer that sample contained humidity prepared by the present embodiment 1 is the crystallization water;This hair
Other every Testing index of bright embodiment 1 are also significantly better than comparative example 1 and comparative example 2, have absolutely proved prepared by the present invention
1/20 water Ribavirin compound stability is more preferable, and quality is better than similar product.
The freeze-drying test of test example 2
The Ribavirin compound that the present inventor prepares embodiment 1, comparative example 1, comparative example 2 is freeze-dried.
Ribavirin compound prepared by embodiment 1, comparative example 1, comparative example 2 is sub-packed in cillin bottle with 0.25g/ bottles, is placed in
Freeze drier, under vacuum condition -40 DEG C of dryings for 24 hours, the moisture variation of detection freeze-drying front and back.
As a result as follows:
Conclusion: moisture does not occur bright after 1/20 water Ribavirin compound prepared by the embodiment of the present invention 1 is freeze-dried
Aobvious variation, Ribavirin compound moisture prepared by comparative example 1, comparative example 2 are substantially reduced, and can speculate Ribavirin of the present invention
Closing the moisture in object is the crystallization water, and the moisture in comparative example 1,2 Ribavirin of comparative example is absorption water.
3 tabletting stability of test example
The Ribavirin compound that the present inventor prepares embodiment 1, comparative example 1, comparative example 2 is pressed into tablet press machine
The circular piece of 0.5g/ piece carries out acceleration investigation.Temperature is 40 DEG C ± 2 DEG C, places 6 months, takes respectively at 0,1,2,3,6 the end of month
Sample.Inspection target is moisture.
Conclusion: the tablet accelerated test moisture of 1/20 water Ribavirin compound compacting prepared by the embodiment of the present invention 1 is not
Significant change occurs, comparative example 1, the tablet moisture that the Ribavirin compound of comparative example 2 is suppressed are substantially reduced, and can reason out this
Moisture in invention Ribavirin compound is the crystallization water, and the moisture in comparative example 1,2 Ribavirin of comparative example is absorption water.
Claims (4)
1. a kind of 1/20 water Ribavirin compound, which is characterized in that every mole of Ribavirin contains 1/20 mole of water, and molecular formula is
C8H12N4O5·1/20H2O, molecular weight 245.11, structural formula is as follows:
2. a kind of pharmaceutical composition, it is characterised in that include 1/20 water Ribavirin compound described in claim 1.
3. a kind of pharmaceutical composition, it is characterised in that include 1/20 water Ribavirin compound described in claim 1 and pharmacy
The excipient of upper receiving.
4. pharmaceutical composition according to claim 3, it is characterised in that described pharmaceutical composition is selected from pharmaceutically acceptable
Dosage form.
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CN109134565A (en) * | 2017-08-15 | 2019-01-04 | 李双喜 | 1/10 water Ribavirin compound of one kind and its pharmaceutical composition |
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CN101891786A (en) * | 2010-08-04 | 2010-11-24 | 王明 | Ribavirin compound and new preparation method thereof |
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CN109134565A (en) * | 2017-08-15 | 2019-01-04 | 李双喜 | 1/10 water Ribavirin compound of one kind and its pharmaceutical composition |
CN109160930A (en) * | 2017-08-18 | 2019-01-08 | 郝志艳 | An a kind of water Troxerutin compound |
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CN1535277A (en) * | 2001-07-30 | 2004-10-06 | �����ﰲ�ط���������ѧ(�����)�ɷ��� | Process for preparation of L-ribavirin |
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