CN1462754A - Medicinal complex dibaicalin zinc and its preparation method - Google Patents
Medicinal complex dibaicalin zinc and its preparation method Download PDFInfo
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- CN1462754A CN1462754A CN 03137761 CN03137761A CN1462754A CN 1462754 A CN1462754 A CN 1462754A CN 03137761 CN03137761 CN 03137761 CN 03137761 A CN03137761 A CN 03137761A CN 1462754 A CN1462754 A CN 1462754A
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- zinc
- baicalin
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- organic solvent
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- 239000011701 zinc Substances 0.000 title claims abstract description 64
- 229910052725 zinc Inorganic materials 0.000 title claims abstract description 64
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims description 11
- 229960003321 baicalin Drugs 0.000 claims abstract description 110
- IPQKDIRUZHOIOM-UHFFFAOYSA-N Oroxin A Natural products OC1C(O)C(O)C(CO)OC1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC=CC=1)O2 IPQKDIRUZHOIOM-UHFFFAOYSA-N 0.000 claims abstract description 108
- AQHDANHUMGXSJZ-UHFFFAOYSA-N baicalin Natural products OC1C(O)C(C(O)CO)OC1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC=CC=1)O2 AQHDANHUMGXSJZ-UHFFFAOYSA-N 0.000 claims abstract description 108
- IKIIZLYTISPENI-ZFORQUDYSA-N baicalin Chemical compound O1[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC=CC=1)O2 IKIIZLYTISPENI-ZFORQUDYSA-N 0.000 claims abstract description 105
- 239000000243 solution Substances 0.000 claims abstract description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 24
- 238000003756 stirring Methods 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000000725 suspension Substances 0.000 claims abstract description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 12
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 8
- 150000003751 zinc Chemical class 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 3
- 238000001914 filtration Methods 0.000 claims abstract description 3
- 238000005406 washing Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 17
- 239000004246 zinc acetate Substances 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 13
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 9
- 230000003115 biocidal effect Effects 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- -1 zinc halide Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims description 3
- 229960001763 zinc sulfate Drugs 0.000 claims description 3
- 229910000368 zinc sulfate Inorganic materials 0.000 claims description 3
- 239000003699 antiulcer agent Substances 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 6
- 239000000203 mixture Substances 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 2
- 230000000767 anti-ulcer Effects 0.000 abstract description 2
- 239000012266 salt solution Substances 0.000 abstract 1
- 230000009102 absorption Effects 0.000 description 21
- 238000010521 absorption reaction Methods 0.000 description 21
- 150000002500 ions Chemical class 0.000 description 19
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 16
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 14
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 12
- 239000011521 glass Substances 0.000 description 10
- 238000002329 infrared spectrum Methods 0.000 description 10
- 241000196324 Embryophyta Species 0.000 description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
- 238000001556 precipitation Methods 0.000 description 9
- 241000972773 Aulopiformes Species 0.000 description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
- 235000019515 salmon Nutrition 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000000536 complexating effect Effects 0.000 description 7
- 229930003944 flavone Natural products 0.000 description 7
- 235000011949 flavones Nutrition 0.000 description 7
- 239000012452 mother liquor Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000011592 zinc chloride Substances 0.000 description 6
- 235000005074 zinc chloride Nutrition 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 235000011194 food seasoning agent Nutrition 0.000 description 5
- 238000003760 magnetic stirring Methods 0.000 description 5
- 238000012856 packing Methods 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 150000002213 flavones Chemical class 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 229920000742 Cotton Polymers 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Natural products OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- 206010068676 Pneumoretroperitoneum Diseases 0.000 description 1
- 208000005727 Retropneumoperitoneum Diseases 0.000 description 1
- 240000004534 Scutellaria baicalensis Species 0.000 description 1
- 235000017089 Scutellaria baicalensis Nutrition 0.000 description 1
- DBJUEJCZPKMDPA-UHFFFAOYSA-N acetic acid;zinc Chemical class [Zn].CC(O)=O DBJUEJCZPKMDPA-UHFFFAOYSA-N 0.000 description 1
- BLAKAEFIFWAFGH-UHFFFAOYSA-N acetyl acetate;pyridine Chemical compound C1=CC=NC=C1.CC(=O)OC(C)=O BLAKAEFIFWAFGH-UHFFFAOYSA-N 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000010165 autogamy Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000003859 hyphenated technique Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- CSJDCSCTVDEHRN-UHFFFAOYSA-N methane;molecular oxygen Chemical compound C.O=O CSJDCSCTVDEHRN-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 229940126680 traditional chinese medicines Drugs 0.000 description 1
- RZLVQBNCHSJZPX-UHFFFAOYSA-L zinc sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Zn+2].[O-]S([O-])(=O)=O RZLVQBNCHSJZPX-UHFFFAOYSA-L 0.000 description 1
- YTSDVWYUJXKXCC-UHFFFAOYSA-L zinc;2-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Zn+2].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O YTSDVWYUJXKXCC-UHFFFAOYSA-L 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A medical complex, bibaicalin zinc, used for preparing antibacterial, anti-inflammatory and anti-ulcerative medicines is prepared through mixing baicalin with water and/or organic solvent to obtain suspension, preparing the solution of zinc salt, adding the zinc salt solution to the suspension while stirring, laying aside, filtering to obtain deposit, washing with mixture of alcohol and water and drying. Its advantages are simple process, and stable activity.
Description
Technical field
The present invention relates to a kind of medical compounds, more particularly, the present invention relates to the complex compound of a kind of baicalin and zinc, the invention still further relates to the preparation method and the application of described complex compound.
Background technology
Baicalin is the main effective constituent of baikal skullcap root, has the pharmacologically active of antibacterial preferably, anti-inflammatory, anti-allergic.Zine ion has converging action, extensively is present among the various mineral drugs.Simultaneously, zinc is one of trace element important in the human body.The complex compound of baicalin and zinc has stronger antibiotic, anti-inflammatory and analgesic activity (referring to " time precious traditional Chinese medical science traditional Chinese medicines, 1999,10 (2): 152 ").The baicalin zinc complex has stability preferably simultaneously.
Structurally may there be difference in the baicalin that different reaction conditionss obtains and the complex compound of zinc.Human baicalins such as Feng Jinming add in the apparatus,Soxhlet's, the methanol solution of zinc acetate is refluxed, the methyl alcohol of evaporation progressively makes it baicalin dissolving and the zinc acetate reaction, and electricity consumption leads-and aglucon/metal curve records that the ratio of baicalin and zinc is 1 to 1 in the complex compound of prepared baicalin and zinc; But determine to participate in the aglucon functional group (referring to " herbal medicine 1998,19 (11): 9 ") of formation coordinate bond.(publication number: the complex compound that has prepared 6 of baicalin ' position carboxyl and zinc ion coordination with the alkaline aqueous solution and the saturated acetic acid zinc reactant aqueous solution of baicalin CN 1244533A), zine ion is 1 to 1 with the mol ratio of baicalin to Chinese patent application.The mol ratio that people such as Fang Yu have prepared baicalin and zinc is 2 to 1 complex compound, but determines the concrete structure (referring to " Shaanxi Normal University journal (natural science edition), 1990,18 (2): 40 ") of prepared complex compound.Have two bigger difficult problems among the above-mentioned preparation technology, one must dissolve baicalin.Baicalin solvability under neutrality, acidic conditions is little, soluble in water or a certain proportion of alcohol solution under alkaline condition, but unstable, be unfavorable for guaranteeing the industrial production product quality stability.Its two, the baicalin zinc of above-mentioned prepared is difficult to filter when cleaning excessive zine ion, has reduced industrial efficient.
Summary of the invention
The objective of the invention is at baicalin solvability under neutral, acidic conditions little, unsettled characteristics under alkaline condition; Screen two baicalin zinc complexes that a kind of preparation technology is easy, structure is clear, activity stabilized, stable and controllable for quality and preparation method thereof.
A kind of medicinal complex compound two baicalin zinc provided by the invention, its chemical structural formula is shown in (I):
Two baicalin zinc of the present invention can prepare as follows:
(1) baicalin is mixed with into the baicalin suspension liquid with water, organic solvent or water with the mixed solution of organic solvent;
(2) zinc salt is water-soluble, methyl alcohol, ethanol, acetone, or be prepared into zinc solution in the mixing solutions of above-mentioned solvent;
(3) under stirring condition, zinc solution is joined in the baicalin suspension liquid;
(4), obtain throw out with reaction mixture sat, filtration;
(5) water and described organic solvent mixing solutions washing precipitate repeatedly, drying promptly obtains two baicalin zinc.
In the method for the present invention, the organic solvent described in its step (1) adopts methyl alcohol, ethanol or acetone.
In the method for the present invention, the mixing solutions of water described in its step (1) and organic solvent adopts 30～90% aqueous ethanolic solutions.
In the method for the present invention, described zinc salt adopts any of zinc acetate, zinc sulfate, zinc nitrate or zinc halide.
The present invention also provides the application in the medicine of a kind of complex compound two baicalin zinc aspect antibiotic, the anti-inflammatory of preparation, antiulcer agent.
The production technique of preparation two baicalin zinc provided by the invention need not to control the pH value in process of production, and preparation technology is easy, has guaranteed starting material stability in process of production, lays a good foundation for the medicine that the quality of production is stable, has improved production efficiency.The structure of product is clear, activity stabilized, stable and controllable for quality.Two prepared baicalin zinc are gathered into loose porous bulk, are orange-yellow to orange red, and methods such as, liquid phase mass spectrometric hyphenated technique synthetic through solid-state nuclear magnetic resonance carbon spectrum, infrared spectra, chemical derivative identify that its structure is two baicalin zinc.Pharmacological evaluation shows, described two baicalin zinc have analgesia preferably, antibiotic, anti-inflammatory, antiulcer activity.
Embodiment:
Structure is identified:
Two baicalin zinc complexes, orange-yellow to orange red unformed powder, powder X-ray-diffraction analysis is shown as amorphousness.Water insoluble, methyl alcohol, ethanol, acetone and other organic solvent are slightly soluble in DMSO, pyridine, DMF, DMAC equal solvent and decomposition.
1, determining of complexing site:
(1), the comparison of baicalin and baicalin zinc complex infrared spectra
The infrared spectra of baicalin (I) shows wave number 1735 (the flexible vibrations of carboxylic acid carbonyl) and 1644 strong absorbing features peaks such as (the flexible vibrations of flavones carbonyl).The above-mentioned absorption peak of prepared baicalin and the complex compound of zinc (II) disappears, and the wide blunt peak of the 1623-1500 of generation is relevant with the later absorption that produces of zine ion complexing with 5 hydroxyls with 3 carbonyls of baicalin.The absorption of 6 ' position carboxyl disappear have two kinds may: one, carboxyl and zine ion formation complex compound, its two, carboxyl is ionized into negative ion.This moment, the absorption red shift to 1600 of carbonyl produced a strong and wide absorption band.So the absorption that produces after the absorption band at the 1623-1500 place in the infrared spectra of II and 4 carbonyls and the zine ion complexing and the absorption of carboxyl negative ion are relevant.Overlap with above-mentioned absorption peak 1608,1572 (containing the flexible vibrations of substituent phenyl ring C=C of lone electron pair) of baicalin.
(2), the research of 3 of baicalin carbonyls and 5 hydroxyl complexing actions
Baicalin and pyridine, propyl carbinol are refluxed altogether, and steaming desolventizes, and gets jelly, uses petroleum ether precipitation, gets baicalin 6 ' butyl ester (III), and the infrared spectra of III and I compares, and carboxyl becomes ester carbonyl group, and the wave number of the two key stretching vibrations of carbon oxygen is by 1725 violet shifts to 1735; The ketone carbonyl, the wave number of absorption peaks such as the two keys of phenyl ring changes little, has verified previous ownership to the I infrared spectra.React with zinc acetate 3, get salmon precipitation (IV).The infrared spectra of IV is compared with III, and the absorption of flavones carbonyl disappears, and the absorption of ester carbonyl group keeps.The infrared spectra of IV is compared with I, and there is strong absorption spike at wave number 1742 places, is the ester carbonyl group absorption peak; 4 carbonyl absorption disappear, and produce the absorption peak of carbonyl and zine ion complexing at 1633 places.The infrared spectra of IV is compared with II, and there is strong absorption spike at wave number 1742 places, is the ester carbonyl group absorption peak, and all the other absorptions are close.Hence one can see that, and 6 of baicalin ' position carbonyl is not participated in reaction in the reaction that forms described two baicalin zinc.VI is dissolved in the EDTA methanol solution carries out the LC/MS/MS analysis, can detect the signal of EDTA (mass-to-charge ratio 291), EDTAZn (mass-to-charge ratio 373) and III.Illustrate that also ester carbonyl group does not participate in complex reaction in the production process of IV.
With baicalin and aceticanhydride-pyridine solution prepared in reaction C5, the acetylize of C6 position, with 5,6,2 ', 4 '-tetrahydroxy-5 ', 3 '-lactone-baicalin is main derivative (V).V is prepared zinc complex by the described method of IV, get salmon precipitation (VI).The VI infrared spectra is compared with I, and the infrared absorption of flavones carbonyl disappears, and the absorption of lactone keeps.VI is dissolved in the methanol solution of EDTA, analyzes with LC/MS/MS, the result shows that 5 ester bond dissociates on the flavones parent nucleus when forming complex compound.4 carbonyls and 5 hydroxyls that baicalin is described have stronger complex ability to the metallic zinc ion.
2, metal ion and aglucon ratio measuring in the complex compound of baicalin and zinc:
In the methyl alcohol of EDTA or the aqueous solution, add the mixture of described baicalin and zinc, the reaction that baicalin and EDTA compete zine ion then takes place.When EDTA and zine ion equivalent, the complex compound of described baicalin and zinc dissolves fully.If add zine ion this moment again, then regenerate salmon precipitation.The ability that EDTA competition zinc is described is better than baicalin.
(1), the preparation of baicalin, EDTA, zinc acetate standardized solution
Respectively accurate weighing one water acetic acid zinc 1.0005 grams, EDTA 1.1250 grams, 50 milligrams of baicalins, put into small beaker respectively, zinc acetate, EDTA add the suitable quantity of water dissolving, and the baicalin dissolve with methanol is transferred to 100 milliliters of volumetric flasks respectively, zinc acetate and baicalin be with methyl alcohol, EDTA water constant volume, and it is standby to be mixed with mother liquor.
Accurately measure 1.000 milliliters in zinc acetate mother liquor, to 10 milliliters of volumetric flasks, the water constant volume gets zinc acetate solution A; Get 1.000 milliliters in EDTA mother liquor, be settled to 10 milliliters, be mixed with the EDTA solution B.Above-mentioned solution for standby.
(2), baicalin is in the comparison of EDTA to the competitive capacity of zine ion
Get zinc acetate mother liquor 140 microlitres respectively, EDTA mother liquor 300 microlitres, 1. baicalin mother liquor 20 microlitres are pressed the order of zinc acetate-EDTA-baicalin and are mixed; 2. pressing the order of zinc acetate-baicalin-EDTA mixes.Measure respectively 1. and the LC/MS response intensity of baicalin, zinc-EDTA and free EDTA 2..The result shows, under two kinds of different order by merging conditions, and the response basically identical of three kinds of signals.Explanation under the excessive condition of EDTA, baicalin fully not with the zine ion complexing.
(3), the zine ion working curve is measured
Zinc ion concentration is respectively 10,20,50,100,200,500 mcg/ml; Linear equation is Y=50864.4+10405.3X, and R=0.99552 illustrates in this scope internal linear good.
(4), the baicalin working curve is measured
The concentration of baicalin is 0.020,0.040,0.100,0.200,0.500 mg/ml; Linear equation is Y=8.56254E6+3.16701E7, and R=0.98007 illustrates in this scope internal linear good
(5), the mensuration of contained zine ion of the complex compound of described baicalin and zinc and baicalin
The complex compound of accurate weighing baicalin and zinc is 1.001 milligrams and 2.497 milligrams respectively, add 0.3 milliliter in EDTA mother liquor, 5 milliliters in water, supersound process is dissolved it fully, adds methanol constant volume to 20 again and milliliter records zinc ion concentration respectively and be respectively 0.565 and 1.045uM/ml; The concentration of baicalin is respectively 0.919 and 1.933uM/ml.Baicalin is 2 to 1 with the ratio of zine ion in the described complex compound.
3, baicalin and two baicalin zinc complex NMR analyze
Baicalin
13C-NMR ownership: baicalin
13C-NMR shows 21 carbon signals altogether, wherein, and 1 carboxyl signal, 1 flavones carbonyl signal, 14 aromatic carbon atom signals (flavones parent nucleus), 4 even oxygen saturation carbon atom signal and 1 sugared end group carbon atom signal (gluconic acid).
The solid of baicalin zinc complex I
13C-NMR and baicalin
13C-NMR compares, and carboxyl illustrates that to high field displacement 2ppm carboxylic ionsization becomes corresponding negative ion.4 ketone carbonyls of flavones were intramolecular hydrogen bond originally, and chemical displacement value is 107.0ppm, formed after the complex compound, to high field displacement 5ppm, illustrated that this position has participated in complexing.Described complex compound
13Be also shown in a pair of signal of 207ppm and 48ppm in the C-NMR spectrum in addition,, determine that the two belongs to the rotation wing of 128ppm place carbon signal by changing rotation frequency.The signal that the 22ppm place shows is the rotation wing of 71ppm place carbon signal.Described complex compound
13C-NMR is consistent with baicalin, does not have the signal of other composition.
The above analysis: in the composition of the complex compound of described baicalin and zinc except other organic composition of baicalin thing; Baicalin is 2 to 1 with the mol ratio of zine ion; 4 carbonyls and 5 hydroxyls of baicalin participate in forming coordinate bond, and 5 ' position carboxyl exists with the ionic form.The complex compound called after two baicalin zinc of described baicalin and zinc.
The experiment of 1: two baicalin zinc of pharmacological evaluation analgesic activity
Material therefor:
Medicine: two baicalin zinc, self-control; Aspirin tablet (Tong Detang), commercially available; 0.6% acetic acid, autogamy.
Animal: kunming mice
Method and result:
Medicine suspends with 0.9% physiological saline, shakes up before the filling stomach.Mouse is divided four groups, 6 every group.1 group is blank, and 2,3 groups is the medicine group, and 4 groups is the acetylsalicylic acid positive controls.Gastric infusion 500 micrograms/kg body weight, blank group is irritated the sodium chloride aqueous solution of stomach 0.9, and 30 minutes pneumoretroperitoneums are injected 0.02 milliliter of 0.6% acetum/only, and that observes mouse in 20 minutes turns round the body number.The result: blank group mouse writhing number of times is 20 ± 5; Drug component is not 8 ± 4,4 ± 4; Inhibiting rate is respectively 60% and 80%.Positive controls is 14 ± 2, and inhibiting rate is 30%.The above results shows that two baicalin zinc have analgesic effect preferably.
The experiment of 2: two baicalin zinc of pharmacological evaluation anti-inflammatory action
Material therefor:
Medicine: two baicalin zinc, self-control; PIKANG SHUANG ointment, commercially available; Dimethylbenzene, analytical pure, Beijing Chemical Plant.
Animal: kunming mice
Method and result:
Mouse is divided 3 groups, 6 every group.1 group is blank, and 2 groups is the medicine group, and 3 groups is the PIKANG SHUANG positive controls.
First group of mouse smeared dimethylbenzene with cotton swab on the inside and outside two sides of left ear, as negative control; Earlier 5 milligram of two baicalin zinc is added in 10 milliliters of dimethylbenzene, the dimethylbenzene that is added with two baicalin zinc is smeared on second treated animal two sides inside and outside left ear; Respectively at smearing two baicalin zinc powders smearing the dimethylbenzene place after 1,2,3 hour.The 3rd treated animal is earlier smeared dimethylbenzene with cotton swab on the inside and outside two sides of left ear, smears PIKANG SHUANG smearing the dimethylbenzene place after half an hour.With sacrifice of animal, measure the weight of mouse left and right sides ear corresponding site with punch method after causing scorching 4 hours.The difference of left and right sides ear weight is the swelling degree.The result: blank group swelling degree is 18.6 ± 0.8; The medicine group is 11.6 ± 2.1; Positive controls is 11.7 ± 1.3.The above results shows that two baicalin zinc have anti-inflammatory action preferably.
Embodiment 1
Baicalin (purity 95%) is commercially available; The analytical pure Zinc Sulphate Heptahydrate is that two swallow chemical plant, Beijing produce; Analytical pure methyl alcohol is that the Beijing Chemical Plant produces.
Baicalin 5.00 grams add 250 milliliters of round-bottomed flasks, add 100 milliliters in water, are positioned on the magnetic stirring apparatus, and are fixing.Zinc sulfate 5.91 grams, with the dissolving of 150 ml methanol, the 250 milliliters of separating funnels of packing into are standby, and the separating funnel frame is in the round-bottomed flask top.Regulate stirring velocity, solid is fully disperseed, continue to stir 20 minutes.Dropwise add zinc solution, have this moment salmon precipitation to generate in the solution immediately.Continue to drip zinc solution to adding fully.Stop to stir, placed 1 hour.Just go out supernatant liquor, residuum is stirred with glass stick make its suspension, go into to be placed with the triangular funnel of filter paper just, normal pressure filters.Treat that liquid filtered, add about 30 milliliter of 60% methanol aqueous solution, and stir with glass stick and to make solid suspension, leave standstill.Repeat said process 3 times, placement, seasoning obtain orange/yellow solid 5.04 grams.Through being accredited as two baicalin zinc.
Embodiment 2
Baicalin (purity 95%) is commercially available, and analyzing single water acetic acid zinc is that two swallow chemical plant, Beijing produce; Edible ethanol (95%), the Beijing Chemical Plant.
Baicalin (purity 95%) 4.46 grams add 250 milliliters of round-bottomed flasks, add 100 milliliters of water 30% ethanolic solns, are positioned on the magnetic stirring apparatus, and are fixing.Zinc acetate 1.11 grams, with 100 milliliter of 30% dissolve with ethanol solution, the 250 milliliters of separating funnels of packing into are standby, and the separating funnel frame is in the round-bottomed flask top.Regulate stirring velocity, solid is fully disperseed, continue to stir 20 minutes.Dropwise add zinc acetate solution, have this moment salmon precipitation to generate in the solution immediately.Continue to drip zinc acetate to adding fully.Stop to stir, placed 1 hour.Just go out supernatant liquor, residuum is stirred with glass stick make its suspension, go into to be placed with the triangular funnel of filter paper just, normal pressure filters.Treat that liquid filtered, add about 30 milliliter of 60% aqueous ethanolic solution, and stir with glass stick and to make solid suspension, leave standstill.Repeat said process 3 times, placement, seasoning obtain orange/yellow solid 4.07 grams.Through being accredited as two baicalin zinc.
Embodiment 3
Reagent and material:
Baicalin (purity 95%), commercially available; Zinc chloride, acetone are analytical pure, and the Beijing Chemical Plant produces; Edible ethanol (95%)
Baicalin (purity 95%) 5.12 grams add 250 milliliters of round-bottomed flasks, add 100 milliliters of 60% ethanolic solns, are positioned on the magnetic stirring apparatus, and are fixing.Zinc chloride 3.01 grams, with 150 milliliter of 30% aqueous acetone solution dissolving, the 250 milliliters of separating funnels of packing into are standby, and the separating funnel frame is in the round-bottomed flask top.Regulate stirring velocity, solid is fully disperseed, continue to stir 20 minutes.Dropwise add zinc acetate solution, have this moment salmon precipitation to generate in the solution immediately.Continue to drip zinc chloride to adding fully.Stop to stir, placed 1 hour.Just go out supernatant liquor, residuum is stirred with glass stick make its suspension, go into to be placed with the triangular funnel of filter paper just, normal pressure filters.Treat that liquid filtered, add about 30 milliliter of 60% ethanol, and stir with glass stick and to make solid suspension, leave standstill.Repeat said process 3 times, placement, seasoning obtain orange/yellow solid 4.92 grams.Through being accredited as two baicalin zinc.
Embodiment 4
Reagent and material:
Baicalin (purity 95%), commercially available, zinc chloride, acetone are analytical pure, the Beijing Chemical Plant produces.
Baicalin (purity 95%) 5.03 grams add 250 milliliters of round-bottomed flasks, add 100 milliliters of 60% aqueous acetone solutions, are positioned on the magnetic stirring apparatus, and are fixing.Zinc chloride 2.10 grams, with 150 milliliter of 30% aqueous acetone solution dissolving, the 250 milliliters of separating funnels of packing into are standby, and the separating funnel frame is in the round-bottomed flask top.Regulate stirring velocity, solid is fully disperseed, continue to stir 20 minutes.Dropwise add zinc acetate solution, have this moment salmon precipitation to generate in the solution immediately.Continue to drip zinc chloride to adding fully.Stop to stir, placed 1 hour.Just go out supernatant liquor, residuum is stirred with glass stick make its suspension, go into to be placed with the triangular funnel of filter paper just, normal pressure filters.Treat that liquid filtered, add about 30 milliliter of 60% aqueous acetone solution, and stir with glass stick and to make solid suspension, leave standstill.Repeat said process 3 times, placement, seasoning obtain orange/yellow solid 4.72 grams.Through being accredited as two baicalin zinc.
Embodiment 5
Baicalin (purity 95%) is commercially available, and the analytical pure zinc nitrate is that two swallow chemical plant, Beijing produce; Edible ethanol (95%), the Beijing Chemical Plant.
Baicalin (purity 95%) 4.46 grams add 250 milliliters of round-bottomed flasks, add 100 milliliters of water 90% ethanolic solns, are positioned on the magnetic stirring apparatus, and are fixing.Zinc nitrate 3.30 grams, with 100 milliliter of 30% dissolve with ethanol solution, the 250 milliliters of separating funnels of packing into are standby, and the separating funnel frame is in the round-bottomed flask top.Regulate stirring velocity, solid is fully disperseed, continue to stir 20 minutes.Dropwise add zinc acetate solution, have this moment salmon precipitation to generate in the solution immediately.Continue to drip zinc nitrate to adding fully.Stop to stir, placed 1 hour.Just go out supernatant liquor, residuum is stirred with glass stick make its suspension, go into to be placed with the triangular funnel of filter paper just, normal pressure filters.Treat that liquid filtered, add about 30 milliliter of 60% aqueous ethanolic solution, and stir with glass stick and to make solid suspension, leave standstill.Repeat said process 3 times, placement, seasoning obtain orange/yellow solid 3.92 grams.Through being accredited as two baicalin zinc.
Claims (7)
1, a kind of medicinal complex compound two baicalin zinc, its chemical structure are as shown in the formula (I):
2, a kind of method for preparing complex compound two baicalin zinc as claimed in claim 1, this method comprises the steps:
(1) baicalin is mixed with into the baicalin suspension liquid with water, organic solvent or water with the mixed solution of organic solvent;
(2) zinc salt is prepared into zinc solution, solvent for use adopts the mixed solution of a kind of or water and described organic solvent in water, methyl alcohol, ethanol or the acetone;
(3) in the described baicalin suspension liquid that under stirring condition, zinc solution is joined;
(4), obtain throw out with reaction mixture sat, filtration;
(5) the mixed solution washing precipitate of water and described organic solvent repeatedly, drying promptly obtains two baicalin zinc.
3. it is characterized in that in accordance with the method for claim 2: the organic solvent described in the step (1) adopts any of methyl alcohol, ethanol or acetone.
4. it is characterized in that in accordance with the method for claim 2: the mixing solutions of water described in the step (1) and organic solvent adopts 30～90% aqueous ethanolic solutions.
5. it is characterized in that in accordance with the method for claim 2: described zinc salt adopts any in zinc acetate, zinc sulfate, zinc nitrate or the zinc halide.
6, according to the described method of the arbitrary claim of claim 2～5, it is characterized in that: described baicalin is 1 to 0.5～1.5 with the mol ratio of zinc salt.
7, the application in the medicine of complex compound two baicalin zinc as claimed in claim 1 aspect antibiotic, the anti-inflammatory of preparation, antiulcer agent.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516341A (en) * | 2011-11-16 | 2012-06-27 | 西南大学 | Baicalin metal complex and preparation method and application thereof |
| CN105878046A (en) * | 2014-12-11 | 2016-08-24 | 柯得股份有限公司 | Composition For Prevention And Treatment Of Pimples Comprising Complex Salt Of Baicalin And Zinc |
| CN108659082A (en) * | 2018-05-25 | 2018-10-16 | 武汉轻工大学 | A kind of preparation method for treating grice diarrhoea scutelloside Zn complex |
| CN111000896A (en) * | 2019-12-30 | 2020-04-14 | 武汉回盛生物科技股份有限公司 | Method for preparing baicalein metal complex by ore coagulation method and preparation thereof |
| CN111233958A (en) * | 2020-03-23 | 2020-06-05 | 湖南华诚生物资源股份有限公司 | Momordica grosvenori flavin metal zinc complex and preparation method thereof |
| CN114099688A (en) * | 2021-11-23 | 2022-03-01 | 中国医学科学院生物医学工程研究所 | Micro-particles based on coordination of flavonoid polyphenol and zinc ions as well as preparation method and application of micro-particles |
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2003
- 2003-06-24 CN CN 03137761 patent/CN1212330C/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516341A (en) * | 2011-11-16 | 2012-06-27 | 西南大学 | Baicalin metal complex and preparation method and application thereof |
| WO2013071724A1 (en) * | 2011-11-16 | 2013-05-23 | Li Zhubo | Baicalin metal complex and preparation method and application thereof |
| CN102516341B (en) * | 2011-11-16 | 2014-04-09 | 西南大学 | Baicalin metal complex and preparation method and application thereof |
| CN105878046A (en) * | 2014-12-11 | 2016-08-24 | 柯得股份有限公司 | Composition For Prevention And Treatment Of Pimples Comprising Complex Salt Of Baicalin And Zinc |
| CN108659082A (en) * | 2018-05-25 | 2018-10-16 | 武汉轻工大学 | A kind of preparation method for treating grice diarrhoea scutelloside Zn complex |
| CN108659082B (en) * | 2018-05-25 | 2021-09-24 | 武汉轻工大学 | Preparation method of baicalin zinc complex for treating piglet diarrhea |
| CN111000896A (en) * | 2019-12-30 | 2020-04-14 | 武汉回盛生物科技股份有限公司 | Method for preparing baicalein metal complex by ore coagulation method and preparation thereof |
| CN111233958A (en) * | 2020-03-23 | 2020-06-05 | 湖南华诚生物资源股份有限公司 | Momordica grosvenori flavin metal zinc complex and preparation method thereof |
| CN114099688A (en) * | 2021-11-23 | 2022-03-01 | 中国医学科学院生物医学工程研究所 | Micro-particles based on coordination of flavonoid polyphenol and zinc ions as well as preparation method and application of micro-particles |
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| Publication number | Publication date |
|---|---|
| CN1212330C (en) | 2005-07-27 |
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