CN102336773B - Baicalin-copper complexes and preparation methods thereof - Google Patents
Baicalin-copper complexes and preparation methods thereof Download PDFInfo
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- CN102336773B CN102336773B CN201110076789.5A CN201110076789A CN102336773B CN 102336773 B CN102336773 B CN 102336773B CN 201110076789 A CN201110076789 A CN 201110076789A CN 102336773 B CN102336773 B CN 102336773B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 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 description 89
- 229960003321 baicalin Drugs 0.000 claims description 89
- 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 description 89
- 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 description 88
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 28
- SZMVKWFJCYTPOI-UHFFFAOYSA-N baicaline Natural products N1CCC2=C3OCOC3=C(OC)C3=C2C1CC1=C3C=C(OC)C(OC)=C1 SZMVKWFJCYTPOI-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 150000004699 copper complex Chemical class 0.000 claims description 22
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 229960003280 cupric chloride Drugs 0.000 claims description 14
- NWFNSTOSIVLCJA-UHFFFAOYSA-L copper;diacetate;hydrate Chemical compound O.[Cu+2].CC([O-])=O.CC([O-])=O NWFNSTOSIVLCJA-UHFFFAOYSA-L 0.000 claims description 12
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 11
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 11
- 238000001556 precipitation Methods 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 10
- 229960000355 copper sulfate Drugs 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 3
- 238000002474 experimental method Methods 0.000 abstract description 10
- 229910052751 metal Inorganic materials 0.000 abstract description 10
- 239000002184 metal Substances 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 6
- 230000003385 bacteriostatic effect Effects 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 2
- 230000007721 medicinal effect Effects 0.000 abstract description 2
- 239000003674 animal food additive Substances 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 45
- 238000010521 absorption reaction Methods 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 32
- 239000000047 product Substances 0.000 description 27
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 22
- 239000010949 copper Substances 0.000 description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 21
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- 229910052802 copper Inorganic materials 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 229910021645 metal ion Inorganic materials 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 7
- 229930182478 glucoside Natural products 0.000 description 7
- 150000008131 glucosides Chemical class 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 241000191967 Staphylococcus aureus Species 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 150000001793 charged compounds Chemical class 0.000 description 5
- 229910001431 copper ion Inorganic materials 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 150000002500 ions Chemical group 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- -1 baicalin glucosides Chemical class 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 230000000536 complexating effect Effects 0.000 description 2
- 150000001879 copper Chemical class 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000013467 fragmentation Methods 0.000 description 2
- 238000006062 fragmentation reaction Methods 0.000 description 2
- 230000001408 fungistatic effect Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 230000001788 irregular Effects 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- MWYSCIOFRMZGMT-UHFFFAOYSA-N CC(O1)=[O][N]11[O]=C(C(C2C3O)(C2O)OC3OC(CC(C2=C3O)OC(C4=CC=CCC4)=CC2=O)=C3O)O1 Chemical compound CC(O1)=[O][N]11[O]=C(C(C2C3O)(C2O)OC3OC(CC(C2=C3O)OC(C4=CC=CCC4)=CC2=O)=C3O)O1 MWYSCIOFRMZGMT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- JJLJMEJHUUYSSY-UHFFFAOYSA-L Copper hydroxide Chemical compound [OH-].[OH-].[Cu+2] JJLJMEJHUUYSSY-UHFFFAOYSA-L 0.000 description 1
- 239000005750 Copper hydroxide Substances 0.000 description 1
- 102000016942 Elastin Human genes 0.000 description 1
- 108010014258 Elastin Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 235000001018 Hibiscus sabdariffa Nutrition 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 235000005291 Rumex acetosa Nutrition 0.000 description 1
- 240000007001 Rumex acetosella Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- DIZPMCHEQGEION-UHFFFAOYSA-H aluminium sulfate (anhydrous) Chemical compound [Al+3].[Al+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O DIZPMCHEQGEION-UHFFFAOYSA-H 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 229940052810 complex b Drugs 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 229910001956 copper hydroxide Inorganic materials 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000005292 diamagnetic effect Effects 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 229920002549 elastin Polymers 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 229910000360 iron(III) sulfate Inorganic materials 0.000 description 1
- 230000005291 magnetic effect Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- CSJDCSCTVDEHRN-UHFFFAOYSA-N methane;molecular oxygen Chemical compound C.O=O CSJDCSCTVDEHRN-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
- 230000005408 paramagnetism Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000004144 purine metabolism Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000003513 sheep sorrel Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009772 tissue formation Effects 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/08—Copper compounds
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/111—Aromatic compounds
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/116—Heterocyclic compounds
- A23K20/121—Heterocyclic compounds containing oxygen or sulfur as hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Husbandry (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to baicalin-copper complexes and preparation methods thereof, and belongs to the field of chemical pharmacy. Two baicalin-copper complexes with novel structures are prepared from different raw materials in different molar ratios; after the complexes are subjected to in-vitro bacteriostatic experiments, results indicate that the complexes have a high bacteriostatic function; and compared with baicalin-metal complexes disclosed in the prior art, the baicalin-copper complexes have better medicinal effect and can serve as feed additives. The invention also provides preparation methods for the baicalin-copper complexes. The methods are simple, and easy to control; and the final products have high purity.
Description
Technical field
The present invention relates to chemicals field, particularly relate to a kind of baicaline copper complex and preparation method thereof.
Background technology
Baicalin is the important natural drug of a class, Effective Component of Chinese Medicine, and its biological activity is extremely extensive, has the multiple pharmacological effect such as antibacterial, hypoglycemic, antiviral, anti-inflammatory, diuresis, antitumor, resisting oxidation free radical, anti-allergic and spasmolysis.
Fe, Cu be in human body content rank first place respectively, second essential trace element.In body, have multiple important enzyme containing Cu, Cu plays activation to the formation of oxyphorase, promotes absorption and the utilization of iron, significant aspect metabolism, purine metabolism, phosphatide and the nervous tissue formation of synthetic, reticular tissue of transmitting electronics, elastin.
Much research shows, baicalin and proper metal ion can increase its biological effect by Chemical bond chelating, and basic reason may be: 1. the easier donates electrons of more former part is combined with oxyradical, thus the antioxygenation of playing; 2. organic coordination compound is to much to take the enzymatic structure that metal is active centre similar, therewith fermentoid in conjunction with and play a role; 3. title complex set part and metal synergy and produced the pharmacologically active of 1+1 > 2.
Many pharmaceutical chemists have carried out a large amount of structural modification work to baicalin, have obtained the modified structure that active higher or chemical property is more conducive to absorption of human body.
Jia Chaoxia, Wu Qi etc. (referring to " Chinese Journal of Inorganic Chemistry; 1990; 6 (1): 106-108 ") are dissolved in baicalin in 50% methanol solution, under sodium hydroxide alkalescence condition, (pH=7.4) reacts with cupric chloride, obtain brown needle baicalin and close copper (CuB), with dry after 60% methanol wash, its structure is suc as formula shown in (I).
Zhang Sujun etc. (referring to " Nanjing Traditional Chinese Medical College's journal; 1991; 7 (4): 235-236 ") are dissolved in baicalin in ethanol solution, under sodium carbonate alkaline condition, add neutralized verdigris reaction, backflow obtains red-brown powder, and with dry after hot absolute ethanol washing, its structure is suc as formula shown in (II).
From above-mentioned two disclosed documents, can find out, be that cupric ion reacts with baicalin equally, and the structure of the title complex obtaining is diverse, and this compound and consumption thereof with copper ions used has very large relation.But above-mentioned two reactions are all that baicalin is dissolved in alcoholic solution, and compared with the compound of copper ions being reacted with baicalin under weak basic condition, still, under alkaline condition, can produce a large amount of Cu (OH)
2precipitation, this precipitation can with resulting title complex coprecipitation out, with alcohol washing, cannot be removed clean, therefore say, the title complex that above-mentioned two disclosed methods of document obtain is a mixture in fact, can not obtain pure substance, and title complex and precipitation of hydroxide be difficult to separate really, so the purifying of final product is very difficult., in synthesizing and purifying, also there is similar difficulty and shortcoming in the existing title complex report about baicalin and the formation of other metal.
Because can be more with the active group (being hapto) of metal generation coordination reaction in baicalin, can form the title complex of various different structures, in conjunction with the pharmacologically active of baicalin, wish to obtain more different drug effect or the higher baicalin metal complexes of drug effect.
Summary of the invention
For the deficiency in above-mentioned field, the invention provides the baicaline copper complex of novel texture, experiment in vitro shows to have stronger bacteria resistance function, compares with existing disclosed baicaline copper complex, its medicinal effect is better.
The present invention simultaneously also provides the preparation method of baicaline copper complex, and the method is simple, and easy to control, and final product purity is high.
Baicaline copper complex, its structure is suc as formula shown in (III):
The preparation method of baicaline copper complex shown in formula (III), it is characterized in that: baicalin, copper sulfate or cupric chloride are dissolved in respectively in non-aqueous solution, both are that 2: 1,1: 1 or 1: 2 hybrid reaction obtain brown color precipitation in molar ratio, filter, with washing with alcohol number time, dry, described non-aqueous solution is one or more of methyl alcohol, ethanol, ethyl acetate and sherwood oil.
Reaction conditions is: temperature of reaction is 30-80 ℃, and the reaction times is 2-3 hour.
Baicaline copper complex, its structure is suc as formula shown in (IV):
The preparation method of baicaline copper complex shown in formula (IV), it is characterized in that: baicalin, neutralized verdigris are dissolved in respectively in non-aqueous solution, both are mixed to get reddish brown precipitation for 2: 1 or 1: 1, filter, with washing with alcohol number time, dry, described non-aqueous solution is one or more of methyl alcohol, ethanol, ethyl acetate and sherwood oil.
Described reaction conditions is: temperature of reaction is 30-80 ℃, and the reaction times is 2-3 hour.
Above-mentioned baicaline copper complex is as the application of fodder additives
The present invention is divided into two groups by experiment:
(1) baicalin, copper sulfate or cupric chloride are dissolved in respectively in non-aqueous solution, in the ratio of different mol ratio (2: 1,1: 1,1: 2), under certain temperature condition, react 2-3h, obtain brown color precipitation, filter, with washing with alcohol number time, dry, obtain brown color chip solid A.Described non-aqueous solution is one or more cooperations of methyl alcohol, ethanol, ethyl acetate and sherwood oil, and temperature of reaction is 30-80 ℃.
(2) baicalin, neutralized verdigris are dissolved in respectively in non-aqueous solution, in the ratio of different mol ratio (2: 1,1: 1), under uniform temp condition, react 2-3h, obtain reddish brown precipitation, filter, with washing with alcohol number time, dry, obtain red-brown pulverulent solids B.Described non-aqueous solution is one or more cooperations of methyl alcohol, ethanol, ethyl acetate and sherwood oil, and temperature of reaction is 30-80 ℃.
Above-mentioned experimental results show that, the different salt roots of different mol ratio, metal of the same race react what obtain with baicalin may be the compound of same structure, also may be the compound of different structure, the present invention carries out structural characterization with UV, Infra-red, NMR, LC-MS, metallic element analysis etc. respectively by product obtained above, infer the product A that above-mentioned (1) group obtains, its structural formula is as shown in (III); The product B that (2) group obtains, its structural formula is as shown in (IV).
The inventive method is reaction under original pH value after two kinds of raw materials are dissolved respectively, avoided producing the possibility of copper hydroxide under alkaline condition, so the product purity that the inventive method obtains is very high, has saved complicated purification step.
The present invention has also done extracorporeal bacteria inhibitor test by above-mentioned portion of product (baicalin reacts gained title complex A and B with metallic copper), shows to have higher fungistatic effect, can be used as fodder additives and uses.
Embodiment
Embodiment 1:
1-1 synthetic compound
The present invention is divided into two groups by experiment:
(1) baicalin, copper sulfate or cupric chloride are dissolved in respectively in non-aqueous solution, in the ratio of different mol ratio (2: 1,1: 1,1: 2), at reaction 2-3h, obtain brown color precipitation, filter, with washing with alcohol number time, dry, obtain brown color chip solid A.Described non-aqueous solution is one or more cooperations of methyl alcohol, ethanol, ethyl acetate and sherwood oil, and temperature of reaction is 30-80 ℃.
(2) baicalin, neutralized verdigris are dissolved in respectively in non-aqueous solution, in the ratio reaction 2-3h of different mol ratio (2: 1,1: 1).The reaction products therefrom of two kinds of different mol ratio is reddish brown precipitation, filters, and with washing with alcohol number time, dries, and obtains red-brown pulverulent solids B.Described non-aqueous solution is one or more cooperations of methyl alcohol, ethanol, ethyl acetate and sherwood oil, and temperature of reaction is 30-80 ℃.
The synthetic yield of above-mentioned experiment is as follows:
1-2 structural characterization
The ultraviolet of 1-2-1 baicaline copper complex characterizes
The ultraviolet result that 1-2-1-1 dilute alkaline soln dissolves
Title complex is dissolved in 2% NaOH, measures maximum absorption wavelength, the results are shown in Table 1.
Table 1 baicalin and the title complex uv-absorbing in alkaline solution
The ultraviolet result that 1-2-1-2DMSO dissolves
Title complex is dissolved in DMSO, measures maximum absorption wavelength, the results are shown in Table 2.
Table 2 baicalin and the title complex uv-absorbing in DMSO solution
From table 1, table 2, product is slightly different from the uv-absorbing in DMSO in alkali lye, in DMSO, measure owing to having eliminated near DMSO as solvent blank end absorption 200nm, so near absorption 200nm of baicalin and each product disappears in DMSO, in two kinds of different solvents, baicalin and each product are the wavelength of other main absorption peaks slightly different (in DMSO, each material maximum absorption wave long value is slightly larger than the maximum absorption wave long value of each material in alkali lye).
The baicalin of measuring in alkali lye and each material maximum absorption wavelength, baicalin has three place's maximum absorption at 214nm, 275nm and 317nm, and all products all only have two place's uv-absorbing, at 317nm place, absorb and disappear.
The baicalin of measuring in DMSO and each material maximum absorption wavelength, baicalin has two place's maximum absorption at 280nm and 316nm, and it is 292nm that all products all only have place's uv-absorbing, and 316nm place uv-absorbing disappears.
The visible two main absorption peaks in place with respect to baicalin (be 275nm and 317nm in alkali, be 280nm and 316nm in DMSO), the ultraviolet absorption peak generation considerable change of title complex, place's absorption peak disappears, place absorption peak generation red shift.Show that baicalin has really occurred to react with metal ion.The reason that uv-absorbing produces red shift is to make the increase of delocalization degree and the metal ion of electronics in whole molecule have certain electron-withdrawing power after forming title complex, the electronic cloud of conjugate ring system moves to the metal of planar central, the required excitation energy of transition of electron is reduced, so absorption peak generation red shift.
The Infrared Characterization of 1-2-2 baicalin metal complexes
The infrared interpretation of result of baicalin, product A (baicalin: copper sulfate or cupric chloride=2: 1,1: 1 or 1: 2), product B (baicalin: neutralized verdigris=2: 1 or 1: 1) is as follows:
The absorption peak of C=O (stretching) is at 1850-1600cm
-1between.In the infared spectrum of baicalin, the absorption peak (stretching vibration peak) of 4 C=O of baicalin is 1661.05cm
-1, on baicalin glucosides, the carbonyl absorption peak of carboxylic acid is 1726.71cm
-1, and in the infared spectrum of two title complexs, these two C=O absorption peaks broaden and are merged into a peak, red shift is to 1624.26cm respectively
-1, 1621.90cm
-1, 1619.20cm
-1, 1625.84cm
-1, 1620.91cm
-1, 1623.67cm
-1, the reason that causes absorption peak red shift is that the lone-pair electron of oxygen and the unoccupied orbital of metal ion form coordinate bond and metal ion makes electron delocalization and cause the cloud density of the two keys of carbon oxygen to reduce, and force constant is diminished, thereby cause Red Shift Phenomena.Explanation thus, the combining site of baicalin and metal ion may be 4 carbonyl or (with) carbonyl of carboxyl on glucosides.
The free O-H key absorption peak of alcohol, phenol is at 3650-3580cm
-1between, association O-H key absorption peak is at 3400-3200cm
-1between, and the free O-H key 3540-3350cm of carboxylic acid
-1between.Can there is intramolecular hydrogen bond and associate in 5 hydroxyls of baicalin and 4 carbonyls, peak position is in 3400-3200cm
-1between, the free O-H key in hydroxyl position in baicalin on carboxylic acid, peak position is in 3540-3350cm
-1between.Because these O-H absorption peaks are very wide, and also have other locational many hydroxyls, cause these O-H absorption peaks at 3600-3200cm
-1between form a large broad peak, the corresponding position of each O-H of indistinguishable.In baicalin infared spectrum, the large broad peak that these O-H keys form is at 3398.45cm
-1there is absorption peak at place.And in the infared spectrum of title complex, baicalin forms after title complex, this peak is from 3398.45cm
-1be moved to respectively 3412.63cm
-1, 3399.95cm
-1, there is blue shift in absorption peak, illustrates that intramolecular hydrogen bond is destroyed, and on 5 hydroxyls or glucosides there is coordination in hydroxyl and the metal ion of carboxyl as can be seen here.
As can be seen here, 5 of baicalin hydroxyls, 4 carbonyls or (with) there is coordination in carbonyl, hydroxyl and the cupric ion of carboxyl on glucosides.
From ultraviolet and infrared result, all there is noticeable change in ultraviolet and the infrared absorption of the relative raw material of product (baicalin), illustrate that complex reaction has occurred for baicalin and cupric ion, hapto is carbonyl, the hydroxyl of carboxyl on 4 carbonyls, 5 hydroxyls or glucosides.
Because ultraviolet and infrared data only can identify baicalin, complex reaction has occurred and tentatively determined the hapto that complex reaction may occur with metal ion, but the accurate location of the different product generation coordinations that different material different ratios obtains also needs following methods further to identify.
1-2-3 baicaline copper
1h NMR characterizes
Baicalin
1h NMR (DMSO) data are as follows:
δ12.545(s，1H，5-OH)，8.664(s，1H，6-OH)，8.070(d，2H，2′，6′-H)，7.571-7.534(m，3H，3′，4′，5′-H)，7.004(s，1H，8-H)，7.000(s，1H，3-H)，5.289-5.499(m，3H，2″，3″，4″-OH)，5.240(d，1H，1″-H)，4.060(d，1H，″-H)，3.330-3.450(m，3H，2″，3″，4″-H).
Baicaline copper (A)
1h NMR (DMSO) result and being analyzed as follows:
Baicaline copper complex is due to the paramagnetic impact of cupric ion, and peak shape broadens, and signal also dies down, but each displacement place of baicalin relatively, title complex all has respective peaks to occur, the peak (being 5-OH peak) that has 12.6 left and right only disappears, and visible 5-OH is owing to being substituted with its H atom of cupric ion generation coordination.
Due to the impact of cupric ion paramagnetism, peak shape and the signal of product hydrogen spectrum are difficult to judge very accurately concrete structural information, therefore only done a kind of product (baicalin: cupric chloride=1: hydrogen spectrum 1), but be confirmablely, peak shape broadens, signal weaker is the key character on the impact of compound nuclear magnetic spectrum as diamagnetic bivalent cupric ion, cause the hydrogen spectrum information of baicalin that the variation of essence has occurred, illustrate that the successful complexing of cupric ion gets on, and baicaline copper (baicalin: cupric chloride=1: 1) peak (being baicalin 5-OH peak) due to 12.6 left and right disappears, can tentatively determine that this structure is with 5 hydroxyls and cupric ion generation coordination.
1-2-4. copper content testing
The content of copper ion of the different Cu salt complex of baicalin and different mol ratio is in Table 3.
Table 3 baicalin reacts measured content of copper ion result with cupric ion
In each title complex recording, the content of institute's copper ions is tentatively definite, and baicalin and cupric chloride or copper sulfate (2: 1,1: 1,1: 2) and baicalin and the neutralized verdigris product under the ratio of 2: 1 or 1: 1 under three kinds of ratios is a part baicalin complexing a part cupric ion.
1-2-5 physical properties
Baicalin and copper sulfate or cupric chloride are in full accord in different mol ratio (2: 1,1: 1,1: 2) products therefrom proterties, be the whole chip solid of brown color, and be all dissolved in DMSO, DMF, be insoluble in the organic solvents such as methyl alcohol, ethanol, water, ethyl acetate, be all dissolved in NaHCO
3, Na
2cO
3solution and dilute NaOH solution.
It is consistent that baicalin and neutralized verdigris obtain product characters in 2: 1,1: 1 liang of group group experiment of mol ratio, is brown ceramic powder shape solid, and is all dissolved in DMSO, DMF, is dissolved in dilute NaOH solution, but is insoluble to NaHCO
3and Na
2cO
3solution.
Baicalin and Tai-Ace S 150 or aluminum chloride obtain the irregular solid of sorrel at 2: 1 o'clock in mol ratio, 1: 1 or 1: 2 mol ratio obtain orange red irregular solid, the two is all dissolved in DMSO, DMF, is insoluble in the organic solvents such as methyl alcohol, ethanol, water, ethyl acetate, is all dissolved in NaHCO
3, Na
2cO
3solution and dilute NaOH solution.
Baicalin and ferric sulfate or iron(ic) chloride obtain black blocks of solid at 2: 1 o'clock in mol ratio, 1: 1 or 1: 2 mol ratio obtain blackish green blocks of solid, the two is all dissolved in DMSO, DMF, is insoluble in the organic solvents such as methyl alcohol, ethanol, water, ethyl acetate, is all dissolved in NaHCO
3, Na
2cO
3solution and dilute NaOH solution.
The further evaluation of 1-2-6 hapto
According to < < Natural Medicine Chemistry > > (People's Health Publisher, Wu Lijun), flavonoid compound each arrangement of hydroxyl acidity and the solvability in the alkali lye of variant intensity have been determined, the acid arrangement of each group is as follows: carboxylic acid group (COOH) > 7, the general phenol OH of 4 '-bis-OH > 7-OH or 4 '-OH > > 5-OH > 3-OH, containing carboxyl or exist 7 and 4 ' hydroxyl to dissolve in NaHCO simultaneously
3, only containing 7 or 4 ' hydroxyl, dissolve in Na
2cO
3, other hydroxyls are insoluble to NaHCO
3and Na
2cO
3, can only be dissolved in the NaOH of different concns.
Baicalin and copper sulfate, cupric chloride are in full accord in different mol ratio (2: 1,1: 1,1: 2) products therefrom proterties, are the whole chip solid of brown color, and Cu
2+content is also consistent.From infrared qualification result, due to the electrophilic effect of cupric ion, cause carbonyl on carboxylic acid and 4 carbonyl absorption that red shift all occurs and overlapping be broad peak, and the infrared absorption of each hydroxyl is due to all at 3600-3200cm
-1between be a large broad peak, therefore be merely difficult to judge the coordination site of cupric ion with infared spectrum.This reaction gained products therefrom is all dissolved in NaHCO
3, illustrate that carboxyl exists, and according to metal ion content measurement result, in product, baicalin and Cu
2+coordination ratio be 1: 1, visible a part baicalin coordinates a part Cu
2+, because the group of the generable coordination of baicalin is two places: the carbonyl on carboxyl and hydroxyl, 4 carbonyls and 5 hydroxyls, so this reaction is for a part baicalin is with 4 carbonyls and 5 hydroxyls and a part Cu
2+there is coordination.
It is consistent that baicalin and neutralized verdigris obtain product characters in 2: 1,1: 1 liang of group group experiment of mol ratio, is red-brown pulverulent solids, and Cu
2+content is also consistent.Infrared result has also shown that fundamental change has occurred the relative baicalin of title complex, and variation portion is also carbonyl and hydroxyl, but with infared spectrum, is difficult to judge concrete hapto merely with the same also the making because each similar group absorption peak is overlapping of the above results.This reaction products therefrom is dissolved in NaOH, but is insoluble to NaHCO
3and Na
2cO
3solution, illustrate on ring-OH exists, and glucosides-hydrogen of COOH do not exist.And according to metal ion content measurement result, in product, baicalin and Cu
2+coordination ratio be 1: 1, visible a part baicalin coordinates a part Cu
2+, because the group of the generable coordination of baicalin is two: carboxyl, 4 carbonyls and 5 hydroxyls, from infrared carbonyl absorption change and glucosides-hydrogen of COOH does not exist, is that a part baicalin is with the carbonyl on carboxyl and hydroxyl and a part Cu
2+there is coordination.
The LC-MS of 1-2-7 baicaline copper complex characterizes
Baicaline copper complex A, baicaline copper complex B are done to mass spectroscopy, and in mass spectrum, gained molecular ion peak is respectively:
In sum, infer that each structure of matter of gained is as follows:
1, baicalin reacts with different ratios cupric chloride or copper sulfate and obtains structure and be presumed as follows: (this structure relative molecular mass is 589, and copper proportion is 10.70%)
Mass spectroscopy: molion peak position is shown as 590, owing to being (molecule+H
+) pattern, so actual molecular weight is 589, meet completely with said structure molecular weight.When molion is bombarded, due to the cause of ionization, so be shown as 588.The intensity of fragment ion peak 570 is maximum, and 588-570=18 is obviously for molecular ion peak loses (this water molecules should be the coordinated water on metallic copper, so first lose) due to an one's share of expenses for a joint undertaking water.The intensity of fragment peak 475 is also larger, according to 588-18-63-32=475, may be because molecular ion peak loses a part coordinated water (18), a part coordination methyl alcohol (32) and a part cupric ion (63).The peak intensity of fragment peak 361.9 is only second to 570 peak intensity, 361.9=588-18-176-32, visible, this is the another kind of fragmentation pattern of molecular ion peak, and molion loses a part coordinated water (18), a part coordination methyl alcohol (32) and a part glucosides (176).Fragment peak 330.8=588-18-176-32-31, visible this kind of fragmentation pattern be except losing a part coordinated water (18), a part coordination methyl alcohol (32) and a part glucosides (176), be combined on the cupric ion-OCH that also continues to lose a part
3group.Hence one can see that, and this structure coordinates a part cupric ion by a part baicalin, have in addition a part water and two molecule methyl alcohol respectively with cupric ion coordination.
2, baicalin reacts with neutralized verdigris (2: 1,1: 1) and obtains structure and be presumed as follows: (this structure relative molecular mass is 567, and copper proportion is 11.11%)
Mass spectroscopy: molecular ion peak is 568, owing to being (molecule+H
+) pattern, so actual molecular weight is 567, meet completely with said structure molecular weight.
Embodiment 2 effect experiments
Extracorporeal bacteria inhibitor test, bacteriostatic experiment the results are shown in Table 4.
Table 4 bacteriostatic experiment result (MIC value)
* because baicalin and cupric chloride, copper sulfate (2: 1,1: 1,1: 2) products therefrom under three kinds of ratios are same products, antibacterial effect is also identical, therefore row one place's data only.
Due to baicalin and neutralized verdigris, products therefrom under 2: 1,1: 1 ratio is same products to *, and antibacterial effect is also identical, therefore row one place's data only.
Result: from antibacterial result, the fungistatic effect of each title complex all significantly strengthens compared with baicalin, the title complex that wherein baicalin and copper sulfate (or cupric chloride) obtain is respectively 1/5,1/10 of baicalin to streptococcus aureus, colibacillary MIC, and the title complex that baicalin and neutralized verdigris (2: 1 or 1: 1) obtain is respectively 1/10,1/5 of baicalin to streptococcus aureus, colibacillary MIC.
Cai passes the disclosed patent of English (publication number: CN 1462619A) invented a kind of baicalin zinc (structure is that a part baicalin coordinates a part zine ion with carboxyl position) pharmaceutical preparation, there is good antibacterial effect, to the MIC of streptococcus aureus, being 0.63mg/ml, is 5.0mg/ml to colibacillary MIC; The disclosed patent such as Wang Yutian (publication number: CN1634952A) invented a kind of baicalin Zn complex (structure is that two molecule baicalins coordinate three molecule zine ions with carboxyl position, 4 carbonyls and 5 hydroxyls), to the MIC of streptococcus aureus, being 1mg/ml, is > 1mg/ml to colibacillary MIC.And two kinds of baicaline copper complexes inventing in this patent to the inhibition of streptococcus aureus be above-mentioned patent institute invention baicalin title complex 1.26-4 doubly, to colibacillary inhibition be above-mentioned patent institute invention baicalin title complex 2-20 doubly, so two kinds of baicaline copper complexes that this patent is invented demonstrate stronger bacteriostatic activity.
Claims (7)
1. baicaline copper complex, its structure as shown in the formula (III):
2. the preparation method of baicaline copper complex claimed in claim 1, it is characterized in that: baicalin, copper sulfate or cupric chloride are dissolved in respectively in non-aqueous solution, both are that 2:1,1:1 or 1:2 hybrid reaction obtain brown color precipitation in molar ratio, filter, with washing with alcohol number time, dry, described non-aqueous solution is one or more of methyl alcohol, ethanol, ethyl acetate and sherwood oil.
3. the preparation method of baicaline copper complex according to claim 2, wherein the condition of reaction is: temperature of reaction is 30-80 ℃, and the reaction times is 2-3 hour.
4. baicaline copper complex, its structure is suc as formula shown in (IV):
5. the preparation method of baicaline copper complex claimed in claim 4, it is characterized in that: baicalin, neutralized verdigris are dissolved in respectively in non-aqueous solution, both are mixed to get reddish brown precipitation for 2:1 or 1:1 in molar ratio, filter, with washing with alcohol number time, dry, described non-aqueous solution is one or more of methyl alcohol, ethanol, ethyl acetate and sherwood oil.
6. the preparation method of baicaline copper complex according to claim 5, described reaction conditions is: temperature of reaction is 30-80 ℃, the reaction times is 2-3 hour.
7. the baicaline copper complex described in claim 1 or 4 is as the application of fodder additives.
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| CN102516341B (en) * | 2011-11-16 | 2014-04-09 | 西南大学 | Baicalin metal complex and preparation method and application thereof |
| CN104031876A (en) * | 2013-12-31 | 2014-09-10 | 陈一强 | Method of inhibiting staphylococcus aureus virulence factor |
| CN108690110A (en) * | 2018-05-25 | 2018-10-23 | 武汉轻工大学 | The preparation method of one boar mixed feeding scutelloside copper complex |
| CN108794554A (en) * | 2018-05-25 | 2018-11-13 | 武汉轻工大学 | The preparation method of one boar mixed feeding scutelloside manganese complex |
| CN109970800A (en) * | 2019-04-29 | 2019-07-05 | 武汉轻工大学 | A kind of bismuth-scutelloside complex and its preparation method and application |
| CN110003294A (en) * | 2019-04-30 | 2019-07-12 | 武汉轻工大学 | A kind of preparation method of copper cobalt nickel-scutelloside complex |
| CN114015068B (en) * | 2021-11-23 | 2023-02-10 | 中国医学科学院生物医学工程研究所 | Flower-shaped MOF material based on coordination of baicalein and copper ions and preparation method and application thereof |
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Non-Patent Citations (5)
| Title |
|---|
| 张素俊 等.黄芩甙与铜、镍、钴金属离子配合物的合成.《南京中医学院学报》.1991,第7卷(第4期),第235-236、256页. |
| 胡道道 等.汉黄芩素与铜(Ⅱ)、钴(Ⅱ)、镍(Ⅱ)固体配合物的合成、表征及抑菌活性研究.《陕西师大学报（自然科学版）》.1994,第22卷(第1期),第31-34页. * |
| 贾朝霞 等.铜(Ⅱ)-黄芩甙配合物的合成及其对超氧负离子歧化活性研究.《无机化学学报》.1990,第6卷(第1期),第106-108页. |
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| 黄芩甙与铜、镍、钴金属离子配合物的合成;张素俊 等;《南京中医学院学报》;19911231;第7卷(第4期);第235-236、256页 * |
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