CN103570663B - A kind of preparation method of high-purity quercetin - Google Patents
A kind of preparation method of high-purity quercetin Download PDFInfo
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- CN103570663B CN103570663B CN201310608063.0A CN201310608063A CN103570663B CN 103570663 B CN103570663 B CN 103570663B CN 201310608063 A CN201310608063 A CN 201310608063A CN 103570663 B CN103570663 B CN 103570663B
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- rutin
- quercetin
- refining
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- liquid ratio
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- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 title claims abstract description 285
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 title claims abstract description 151
- 235000005875 quercetin Nutrition 0.000 title claims abstract description 142
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 title claims abstract description 141
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 title claims abstract description 141
- 229960001285 quercetin Drugs 0.000 title claims abstract description 141
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- JMGZEFIQIZZSBH-UHFFFAOYSA-N Bioquercetin Natural products CC1OC(OCC(O)C2OC(OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5)C(O)C2O)C(O)C(O)C1O JMGZEFIQIZZSBH-UHFFFAOYSA-N 0.000 claims abstract description 127
- IVTMALDHFAHOGL-UHFFFAOYSA-N eriodictyol 7-O-rutinoside Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C=C3C(C(C(O)=C(O3)C=3C=C(O)C(O)=CC=3)=O)=C(O)C=2)O1 IVTMALDHFAHOGL-UHFFFAOYSA-N 0.000 claims abstract description 127
- FDRQPMVGJOQVTL-UHFFFAOYSA-N quercetin rutinoside Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 FDRQPMVGJOQVTL-UHFFFAOYSA-N 0.000 claims abstract description 127
- ALABRVAAKCSLSC-UHFFFAOYSA-N rutin Natural products CC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5 ALABRVAAKCSLSC-UHFFFAOYSA-N 0.000 claims abstract description 127
- IKGXIBQEEMLURG-BKUODXTLSA-N rutin Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@@H]1OC[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-BKUODXTLSA-N 0.000 claims abstract description 127
- 235000005493 rutin Nutrition 0.000 claims abstract description 127
- 229960004555 rutoside Drugs 0.000 claims abstract description 127
- 238000007670 refining Methods 0.000 claims abstract description 79
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 41
- 239000007788 liquid Substances 0.000 claims abstract description 36
- 239000002904 solvent Substances 0.000 claims abstract description 35
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000012043 crude product Substances 0.000 claims abstract description 32
- 238000009835 boiling Methods 0.000 claims abstract description 20
- 239000012065 filter cake Substances 0.000 claims abstract description 17
- 230000007062 hydrolysis Effects 0.000 claims abstract description 16
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 16
- 238000002425 crystallisation Methods 0.000 claims abstract description 12
- 230000008025 crystallization Effects 0.000 claims abstract description 12
- 238000000967 suction filtration Methods 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims abstract description 9
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 4
- 239000000706 filtrate Substances 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 63
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 50
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 14
- 238000001035 drying Methods 0.000 abstract description 7
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- IYRMWMYZSQPJKC-UHFFFAOYSA-N kaempferol Chemical compound C1=CC(O)=CC=C1C1=C(O)C(=O)C2=C(O)C=C(O)C=C2O1 IYRMWMYZSQPJKC-UHFFFAOYSA-N 0.000 description 21
- 239000000126 substance Substances 0.000 description 15
- GQODBWLKUWYOFX-UHFFFAOYSA-N Isorhamnetin Natural products C1=C(O)C(C)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 GQODBWLKUWYOFX-UHFFFAOYSA-N 0.000 description 13
- IZQSVPBOUDKVDZ-UHFFFAOYSA-N isorhamnetin Chemical compound C1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 IZQSVPBOUDKVDZ-UHFFFAOYSA-N 0.000 description 13
- 239000012535 impurity Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- UBSCDKPKWHYZNX-UHFFFAOYSA-N Demethoxycapillarisin Natural products C1=CC(O)=CC=C1OC1=CC(=O)C2=C(O)C=C(O)C=C2O1 UBSCDKPKWHYZNX-UHFFFAOYSA-N 0.000 description 10
- 238000001514 detection method Methods 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 235000008777 kaempferol Nutrition 0.000 description 10
- UXOUKMQIEVGVLY-UHFFFAOYSA-N morin Natural products OC1=CC(O)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UXOUKMQIEVGVLY-UHFFFAOYSA-N 0.000 description 10
- 239000013558 reference substance Substances 0.000 description 10
- 238000010606 normalization Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000003672 processing method Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000009965 odorless effect Effects 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical compound N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 241000370738 Chlorion Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000000844 anti-bacterial 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
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical class [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- CXQWRCVTCMQVQX-UHFFFAOYSA-N cis-dihydroquercetin Natural products O1C2=CC(O)=CC(O)=C2C(=O)C(O)C1C1=CC=C(O)C(O)=C1 CXQWRCVTCMQVQX-UHFFFAOYSA-N 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- -1 flavonoid compound Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 235000021191 food habits Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/40—Separation, e.g. from natural material; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of preparation method of high-purity quercetin, comprise the steps: A) step of refined rutin: add in the solvent of boiling by certain liquid ratio by rutin, described rutin is dissolved completely, suction filtration while hot, collect filtrate, cooling crystallization, filter and obtain the rutin after refining; B) step of hydrolyzing rutin: sulfuric acid and water are mixed to get sour water mixture, be heated to add the rutin after described refining by certain liquid ratio after seething with excitement, after hydrolysis completely, filter, collect filter cake, be washed to neutrality, drying, obtains Quercetin crude product; C) step of refining Quercetin: by certain liquid ratio described Quercetin crude product added in refining solvent and wash, filter, dry, obtain high-purity quercetin.Compared with prior art, method provided by the invention is simple, and energy consumption is lower, improves the purity of Quercetin, can realize the preparation of highly purified pharmaceutical grade Quercetin.
Description
Technical field
The present invention relates to a kind of preparation method of Quercetin, particularly relate to a kind of preparation method of high-purity quercetin, belong to technical field of plant extraction.
Background technology
Quercetin chemical name is 3,3', 4', 5,7-pentahydroxyflavone, and be vegitabilia's distribution flavonoid compound the most widely, all contain Quercetin in the plant of about 68%, multiple food is all containing this composition.According to the difference of food habits, human body takes in 10 ~ 100mg Quercetin average every day.Quercetin has biological action widely, as antitumor, anti-inflammatory, anti-oxidant, step-down, antibacterial, antiviral, antianaphylaxis, platelet aggregation-against and scavenging free radicals etc.The structural formula of Quercetin is as follows:
Industrially at present carry out hydrolyzing rutin mainly through methods such as enzyme hydrolysis method, Microwave Water solution, high pressure water solution and acid-hydrolysis methods and acquire Quercetin, applying maximum is acid-hydrolysis method.But existing preparation method can not acquire highly purified Quercetin, commercially available Quercetin purity, generally lower than 98.0%, cannot reach the high purity of more than 99.0%.All will through the step of rutin hydrolysis as acid-hydrolysis method, major impurity in the Quercetin obtained after rutin hydrolysis is kaempferol and Isorhamnetol, these two impurity are exist with the form of glucosides in rutin, and along with rutin be hydrolyzed to Quercetin while be hydrolyzed into aglycon, once after formation aglycon, these two impurity (especially Isorhamnetol) are difficult to reduce content by refining method, therefore be difficult to after the purity of Quercetin reaches 98.0% improve further, the purity of further raising Quercetin becomes a technical development bottleneck of the industry, particularly for pharmaceutical grade bulk drug, the further lifting of Quercetin purity has important industrialization meaning.The drug legislation of current China is declared and is generally not less than 98.5% to the purity requirement of bulk drug.Therefore, want Quercetin to be developed to medicinal application in clinical, preparing highly purified bulk drug is primary condition.But the Quercetin that prior art prepares does not reach drug manufacture manufacture requirements in purity.
Summary of the invention
For the deficiency existing for prior art, technical problem to be solved by this invention is the preparation method providing a kind of high-purity quercetin, and the method is simple, and energy consumption is low, and environmental pollution is little.
For realizing above-mentioned object, the present invention adopts following technical scheme:
The invention provides a kind of preparation method of high-purity quercetin, comprise the steps:
A) step of refined rutin, comprising:
Add in the solvent of boiling by certain liquid ratio by rutin, described rutin is dissolved completely, and suction filtration while hot collects filtrate, cooling crystallization, filters and obtains the rutin after refining;
B) step of hydrolyzing rutin, comprising:
Sulfuric acid and water are mixed to get sour water mixture, and be heated to add the rutin after described refining by certain liquid ratio after seething with excitement, after hydrolysis completely, filter, collect filter cake, be washed to neutrality, drying, obtains Quercetin crude product;
C) step of refining Quercetin, comprising:
By certain liquid ratio described Quercetin crude product added in refining solvent and wash, filter, dry, obtain high-purity quercetin.
Preferably, in the step of described refined rutin, described solvent is selected from the one in water, methyl alcohol, ethanol, methanol-water solution or ethanol-water solution.
Wherein more preferably, in the step of described refined rutin, described solvent is water.
Preferably, in the step of described refining Quercetin, described refining solvent is selected from the one in ethyl acetate, acetone, methylene dichloride, methyl alcohol, ethanol, methanol aqueous solution or aqueous ethanolic solution.
Wherein more preferably, in the step of described refining Quercetin, described refining solvent is ethanol.
Further, in the step of described refining Quercetin, the solid-liquid ratio of Quercetin crude product and ethanol is 1kg:10 ~ 20L.
Preferably, in the step of described refined rutin, the solid-liquid ratio of described rutin and described solvent is 1kg:50 ~ 250L.
Wherein more preferably, in the step of described refined rutin, the solid-liquid ratio of described rutin and described solvent is 1kg:180 ~ 200L.
Preferably, in the step of described hydrolyzing rutin, described refining after rutin and the solid-liquid ratio of described sour water mixture be 1kg:15 ~ 50L.
Wherein more preferably, in the step of described hydrolyzing rutin, described refining after rutin and the solid-liquid ratio of described sour water mixture be 1kg:25 ~ 50L.
Outstanding advantages of the present invention is: the present invention is by increasing rutin pre-treatment step refining in specific solvent, and use the crude product of specific refining solvent to Quercetin to refine, can impurity (especially Isorhamnetol) content effectively in control objectives product, make the purity of Quercetin reach more than 99.0%, thus fulfilling medicinal level bulk drug is for the requirement of sample purity and content; And method provided by the invention is simple, easy to control, solvent environmental protection, to be easy to get, greatly can to reduce production cost.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail.
The invention provides a kind of preparation method of high-purity quercetin, comprise the steps: A) step of refined rutin, comprising: by certain liquid ratio, rutin is added in the solvent of boiling, described rutin is dissolved completely, and suction filtration while hot collects filtrate, cooling crystallization, filters and obtains the rutin after refining; B) step of hydrolyzing rutin, comprising: sulfuric acid and water are mixed to get sour water mixture, is heated to add the rutin after described refining by certain liquid ratio after seething with excitement, and after hydrolysis completely, filter, collect filter cake, be washed to neutrality, drying, obtains Quercetin crude product; C) step of refining Quercetin, comprising: to be added in refining solvent by described Quercetin crude product by certain liquid ratio and wash, filter, dry, obtains high-purity quercetin.Detailed description is launched to the preparation method of this high-purity quercetin below:
In embodiments of the invention, Quercetin crude product is the product obtained after hydrolysis; Quercetin finished product is obtain product after Quercetin crude product refining.
The content assaying method of Quercetin:
The assay of Quercetin can adopt high performance liquid chromatography (with reference to Chinese Pharmacopoeia version in 2010), and concrete grammar is as follows:
Take octadecylsilane chemically bonded silica as weighting agent; With methyl alcohol-0.4% phosphate aqueous solution (53:47, v/v) for moving phase; Determined wavelength 366nm, theoretical pedal number calculates should be not less than 5000 by Quercetin peak.
The preparation of reference substance solution: get Quercetin reference substance, adds the solution that chromatogram Methanol becomes 100 μ g/ml, to obtain final product.
The configuration of need testing solution: the Quercetin powder getting refining gained, adds chromatogram methyl alcohol, makes the solution of 100 μ g/ml, to obtain final product.
Measuring method: accurate absorption reference substance solution and each 10 μ l of need testing solution respectively, injection liquid chromatography, record color atlas.
Determination of related substances method in Quercetin finished product:
In Quercetin finished product, the mensuration of related substance also can adopt high performance liquid chromatography, and concrete grammar is as follows:
Need testing solution configures: get Quercetin finished product, add moving phase and dissolve and the solution being diluted to 0.5mg/ml, as need testing solution;
The configuration of mixing reference substance solution:
(1) kaempferol and the configuration of Isorhamnetol reference substance solution: take kaempferol and each 10mg of Isorhamnetol reference substance, put in 100ml measuring bottle, add chromatogram methyl alcohol and make dissolving in right amount, with chromatogram methanol dilution to scale, shake up, obtain impurity kaempferol and Isorhamnetol reference substance solution.
(2) precision measures need testing solution 500 μ l, puts in 100ml measuring bottle, then adds 5ml kaempferol that precision measures and Isorhamnetol reference substance solution is put in 100ml measuring bottle, with chromatogram methanol dilution to scale, shakes up, obtains mixing reference substance solution.
Measuring method: precision measures need testing solution and each 10 μ l of mixing reference substance solution, respectively injection liquid chromatography, record color atlas.The eluent gradient elution time that Quercetin related substance detects is as shown in table 1.
The eluent gradient elution time table that table 1 Quercetin related substance detects
| Time (minute) | Methyl alcohol (%) | 0.1% aqueous formic acid (%) |
| 0 | 10 | 90 |
| 15 | 40 | 60 |
| 30 | 90 | 10 |
| 40 | 90 | 10 |
The preparation of embodiment 1 high-purity quercetin
Add rutin 100g after 20L water being heated to boiling, and keep whipped state to dissolve rutin, dissolve completely until rutin, suction filtration while hot, left at room temperature over night crystallization, filter, dry, obtain the rutin after refining; The rutin after refining is added after the aqueous sulfuric acid of 1% volumn concentration being heated to boiling, rutin after refining and the solid-liquid ratio of aqueous sulfuric acid are 1kg:25L, after hydrolysis completely, filter, collect filter cake, distilled water is washed till neutrality, with pH detection paper, after up to standard, sample is placed in baking oven dry, obtains Quercetin crude product; In Quercetin crude product, add ethanol according to the liquid ratio of 1kg:15L, stir, leave standstill, filter, drying, obtains Quercetin finished product, and the purity of Quercetin finished product is 99.52%, the content of kaempferol is 0.20%, and the content of Isorhamnetol is 0.13%, and its moderate purity calculates with peak area normalization method.
The preparation of embodiment 2 high-purity quercetin
Add rutin 100g after 18L water being heated to boiling, and keep whipped state to dissolve rutin, dissolve completely until rutin, suction filtration while hot, left at room temperature over night crystallization, filter, dry, obtain the rutin after refining; The rutin after refining is added after the aqueous sulfuric acid of 1% volumn concentration being heated to boiling, rutin after refining and the solid-liquid ratio of aqueous sulfuric acid are 1kg:15L, after hydrolysis completely, filter, collect filter cake, distilled water is washed till neutrality, with pH detection paper, after up to standard, sample is placed in baking oven dry, obtains Quercetin crude product; In Quercetin crude product, add methyl alcohol according to the liquid ratio of 1kg:10L, stir, leave standstill, filter, drying, obtains Quercetin finished product, and the purity of Quercetin finished product is 99.50%, the content of kaempferol is 0.25%, and the content of Isorhamnetol is 0.16%, and its moderate purity calculates with peak area normalization method.
The preparation of embodiment 3 high-purity quercetin
Add rutin 100g after 25L water being heated to boiling, and keep whipped state to dissolve rutin, dissolve completely until rutin, suction filtration while hot, left at room temperature over night crystallization, filter, dry, obtain the rutin after refining; The rutin after refining is added after the aqueous sulfuric acid of 1% volumn concentration being heated to boiling, rutin after refining and the solid-liquid ratio of aqueous sulfuric acid are 1kg:50L, after hydrolysis completely, filter, collect filter cake, distilled water is washed till neutrality, with pH detection paper, after up to standard, sample is placed in baking oven dry, obtains Quercetin crude product; In Quercetin crude product, add ethanol according to the liquid ratio of 1kg:20L, stir, leave standstill, filter, drying, obtains Quercetin finished product, and the purity of Quercetin finished product is 99.51%, the content of kaempferol is 0.21%, and the content of Isorhamnetol is 0.14%, and its moderate purity calculates with peak area normalization method.
Embodiment 4 rutin quality is to the impact analysis of the Quercetin finished product purity obtained
Refining rear rutin is adopted to carry out contrast experiment, to investigate the necessity of rutin being carried out to pre-treatment with refining in advance rutin respectively.
Adopt refining after the processing method of rutin: add rutin 100g after 18L water being heated to boiling, and keep whipped state to dissolve rutin, dissolve completely until rutin, suction filtration while hot, left at room temperature over night crystallization, filter, dry, obtain the rutin after refining; The rutin after refining is added after the aqueous sulfuric acid of 1% volumn concentration being heated to boiling, rutin after refining and the solid-liquid ratio of aqueous sulfuric acid are 1kg:25L, after hydrolysis complete (about 4-5h), filter, collect filter cake, distilled water is washed till neutrality, with pH detection paper, after up to standard, sample is placed in baking oven dry, obtains Quercetin crude product; In Quercetin crude product, add ethanol according to the liquid ratio of 1kg:15L, stir, leave standstill, filter, dry, obtain Quercetin finished product.Test in triplicate, the Quercetin purity of gained and final product quality and yield as shown in table 2, Quercetin its related substances is as shown in table 3, and its moderate purity calculates with peak area normalization method.
The not processing method of refined rutin in advance: add rutin 100g after the aqueous sulfuric acid 2.5L of 1% volumn concentration being heated to boiling, hydrolysis obtains being hydrolyzed the Quercetin produced completely, filter, collect filter cake, distilled water is washed till neutrality, with pH detection paper, after up to standard, sample is placed in baking oven dry, obtains Quercetin crude product; In Quercetin crude product, add ethanol according to the liquid ratio of 1kg:15L, stir, filter, dry, obtain Quercetin finished product.Test in triplicate, Quercetin purity and the final product quality yield of gained are as shown in table 2, and Quercetin its related substances is as shown in table 3, and its moderate purity calculates with peak area normalization method.
The Quercetin purity that table 2 adopts the preparation technology of refining rear rutin and non-refined rutin to obtain and yield
The Quercetin its related substances that table 3 adopts the preparation technology of refining rear rutin and non-refined rutin to obtain
As can be seen from table 2 and table 3, adopt refining after rutin prepare Quercetin, the Quercetin that the Quercetin finished product purity of acquisition and being all obviously better than the control of major impurity is prepared without refining rutin.
Embodiment 5 contrasts prior art and carries out refined rutin to the impact analysis improving Quercetin purity
Existing Quercetin preparation technology adopts unpurified rutin as the raw material of acid hydrolysis step usually.By adopting the testing program of prior art, investigate respectively refining after rutin with without the impact of refined rutin on the Quercetin purity prepared and related substance thereof.
Adopt the processing method of prior art: by rutin 100g(1:12, g/ml) add in the aqueous sulfuric acid of 0.616mol/L, keep boiling 2 ~ 3h; Filter, the filter cake temperature obtained after filtration is 60-70 DEG C of water washing, is washed till neutrality, with pH detection paper, after up to standard, dry, obtains Quercetin crude product filter cake; In Quercetin crude product, add methanol solution (1:20, g/ml), stir, leave standstill, filter, 10 times of methanol wash used again by filter cake, are finally washed till colorless and odorless with 5 times of pure water, dry, obtain Quercetin fine work.Test in triplicate, its related substances of Quercetin purity and yield result and Quercetin is as shown in table 4,5.
Prior art basis adds the processing method of refined rutin step: after 20L water being heated to boiling, add rutin 100g, and keep whipped state to dissolve rutin, after rutin is dissolved completely, by rutin solution while hot suction filtration in container, left at room temperature over night crystallization, filter and obtain the rutin sample after refining, drying obtains the rutin after refining, for subsequent use; Rutin (1:12, g/ml) after refining is added in the aqueous sulfuric acid of 0.616mol/L, keeps boiling 2 ~ 3h, filter, the filter cake temperature obtained after filtration is 60-70 DEG C of water washing, is washed till neutrality, with pH detection paper, after up to standard, dry, obtain Quercetin crude product filter cake; In Quercetin crude product, add methanol solution (1:20, g/ml), stir, leave standstill, filter, 10 times of methanol wash used again by filter cake, are finally washed till colorless and odorless with 5 times of pure water, dry, obtain Quercetin fine work.Test in triplicate, result is as shown in table 4,5.
The Quercetin purity that table 4 adopts refined rutin and non-refined rutin technique prior art to prepare and yield
Its related substances of the Quercetin that table 5 adopts refining rear rutin and non-refined rutin to prepare
Result shows, the raising of quercetin content realizes by reducing kaempferol and Isorhamnetol in Quercetin that in rutin, kaempferol-3-rutinose and Isorhamnetol-3-rutinose two related substance and hydrolysis produce; And the Quercetin do not obtained by the rutin that early stage is refining all cannot obtain the Quercetin of high purity (>99.0%).Only can obtain according to the design of experimental example 4 in patent application 201110408133.9 Quercetin that purity is 98.5%, purity cannot reach 99.63% of report at all.
The solvent of embodiment 6 refined rutin is to the impact analysis of the refining rear rutin purity obtained
Add rutin after using different solvents (aqueous ethanolic solution, water that the methanol aqueous solution that methyl alcohol, ethanol, volume ratio are 1:1, volume ratio are 1:1) to be heated to boiling respectively, and keep whipped state to dissolve rutin.Dissolve completely until rutin, suction filtration while hot, left at room temperature over night is to carry out crystallization.The purity of the refining rear rutin of detection and the purity (adopting HPLC peak area normalization method) of major impurity respectively, the content influence result of different refining solvents to the purity and related substance of refining rear rutin is as shown in table 6.
The different refining solvent of table 6 is to the purity of rutin and the content influence situation of related substance after refining
| Refining solvent | Rutin purity | Kaempferol-3-rutinose and Isorhamnetol-3-rutinose |
| Methyl alcohol | 93.21% | 2.80% |
| Ethanol | 93.83% | 2.72% |
| Methanol/water=1/1 | 93.09% | 2.37% |
| Ethanol/water=1/1 | 93.14% | 2.45% |
| Water | 95.47% | 1.49% |
| Nothing | 93.26% | 2.75% |
As can be seen from the above table, according to the purity of refining rear rutin, in conjunction with economy and the feature of environmental protection of refining solvent, the refining solvent effect used water as rutin is best.
The selection analysis of embodiment 7 Quercetin refining solvent
Add rutin 100g after 20L water being heated to boiling, and keep whipped state to dissolve rutin, after rutin dissolving completely, suction filtration while hot, left at room temperature over night crystallization, filters and obtains the rutin after refining, dry, obtains the rutin 70g after refining; Add the rutin after refining after the aqueous sulfuric acid 1.75L of 1% being heated to boiling, after hydrolysis completely, filter, collection filter cake, distilled water is washed till neutrality, with pH detection paper, after up to standard, sample is placed in baking oven drying, obtains Quercetin crude product 36g; Take 50mg Quercetin crude product respectively, add the different solvent of 1.0ml (ethyl acetate, acetone, methylene dichloride, methyl alcohol, ethanol) respectively in sample hose, the centrifugal 3min of ultrasonic 30min, 13000rpm, get supernatant 100 μ l methanol dilution to 1ml, carry out purity testing with liquid relative sample.Quercetin purity and the magazine content of different refining solvent gained are as shown in table 7.The purity peak area normalization method of sample calculates.
The selection of table 7 Quercetin refining solvent
Result shows: use the Quercetin finished product purity that obtains of Ethanol Treatment optimum, and from the angle of suitability for industrialized production environmental protection, ethanol is also optimum selection.
The dosage analysis of embodiment 8 Quercetin refining solvent
Add rutin 100g after 20L water being heated to boiling, and keep whipped state to dissolve rutin, after rutin dissolving completely, suction filtration while hot, left at room temperature over night crystallization, filters and obtains the rutin after refining, dry, obtains the rutin 70g after refining; The aqueous sulfuric acid 1.75L of 1% is heated to add after seething with excitement obtain refining after rutin 70g, after hydrolysis completely, filter, collect filter cake, distilled water is washed till neutrality, with pH detection paper, after up to standard, sample is placed in baking oven dry, obtains Quercetin crude product 36g; Get Quercetin crude product 9g respectively, respectively in 1:5,1:10,1:15 and 1:20(g/ml) feed liquid ratio add ethanol, stir, leave standstill, filter, dry, obtain Quercetin finished product.The solid-liquid ratio of different ethanol purification Quercetins and yield and sample purity experimental result as shown in table 8.The purity peak area normalization method of sample calculates, and mass yield is in Quercetin crude product.Before refining, Quercetin sample purity is 98.21%, and the content of impurity is trifolitin 0.88%, Isorhamnetol 0.63%.
The solid-liquid ratio of table 8 ethanol purification Quercetin and yield and sample purity relation
Result shows, along with the increasing of ethanol usage quantity, the mass yield of Quercetin reduces gradually, and purity increases gradually.Use the ethanol of 15 times amount can get the Quercetin finished product of better quality yield, purity also can reach more than 99.5%, when the ethanol of use 20 times, the purity of Quercetin finished product brings up to 99.64% slightly, but yield is only 45.1%, decline relative to 15 times amount comparatively large, therefore the consumption of Quercetin refining solvent is preferably solid-liquid ratio 1:15.
The Quercetin finished product obtained according to preparation method provided by the invention, quercetin content is greater than 99.0%, can meet the drug legislation of current China and declare requirement to bulk drug content; Meanwhile, in Quercetin finished product, kaempferol content is less than 0.3%, and Isorhamnetol content is less than 0.2%, and other single impurity peak area sums are less than 0.1%, the impurity level of the Quercetin sample finished product that this impurity level is prepared well below prior art; In Quercetin finished product provided by the invention, chlorion, vitriol are all less than 0.005%, heavy metal, arsenic salt, ignition residue detect and are less than 10ppm, 0.5ppm and 0.01% respectively, moisture content is less than 0.5%, and ethanol content is less than 0.5%, the requirement of above test item equal fulfilling medicinal level bulk drug.
The preparation method of high-purity quercetin provided by the invention is simple, and energy consumption is low, and environmental pollution is little, effectively control the content of related substance, the Quercetin finished product purity of preparation and content are all higher than 99.0%, and application prospect is wide, can meet the related request of bulk drug.
Above the preparation method of high-purity quercetin provided by the present invention is described in detail.For one of ordinary skill in the art, to any apparent change that it does under the prerequisite not deviating from connotation of the present invention, all by formation to infringement of patent right of the present invention, corresponding legal obligation will be born.
Claims (5)
1. a preparation method for high-purity quercetin, is characterized in that comprising the steps:
A) step of refined rutin, comprising:
Add in the solvent of boiling by certain liquid ratio by rutin, described rutin is dissolved completely, and suction filtration while hot collects filtrate, cooling crystallization, and filter and obtain the rutin after refining, the solid-liquid ratio of described rutin and described solvent is 1kg:50-250L;
B) step of hydrolyzing rutin, comprising:
Sulfuric acid and water are mixed to get sour water mixture, be heated to add the rutin after described refining by certain liquid ratio after seething with excitement, after hydrolysis completely, filter, collect filter cake, be washed to neutrality, dry, obtain Quercetin crude product, described refining after rutin and the solid-liquid ratio of described sour water mixture be 1kg:15-50L;
C) step of refining Quercetin, comprising:
By certain liquid ratio described Quercetin crude product added in refining solvent and wash, filter, dry, obtain high-purity quercetin;
In the step of described refining Quercetin, described refining solvent is ethanol, and the solid-liquid ratio of Quercetin crude product and ethanol is 1kg:10-20L.
2. the preparation method of high-purity quercetin as claimed in claim 1, it is characterized in that, in the step of described refined rutin, described solvent is selected from the one in water, methyl alcohol, ethanol, methanol-water solution or ethanol-water solution.
3. the preparation method of high-purity quercetin as claimed in claim 1 or 2, it is characterized in that, in the step of described refined rutin, described solvent is water.
4. the preparation method of high-purity quercetin as claimed in claim 1, it is characterized in that, in the step of described refined rutin, the solid-liquid ratio of described rutin and described solvent is 1kg:180-200L.
5. the preparation method of high-purity quercetin as claimed in claim 1, is characterized in that, in the step of described hydrolyzing rutin, described refining after rutin and the solid-liquid ratio of described sour water mixture be 1kg:25-50L.
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| CN104774189A (en) * | 2015-03-31 | 2015-07-15 | 浙江大学 | Method for preparing high-purity quercetin |
| CN108997293B (en) * | 2018-07-20 | 2021-03-26 | 西安惠博生物科技有限公司 | Quercetin crystal and preparation method thereof |
| CN110452207A (en) * | 2019-09-12 | 2019-11-15 | 河北医科大学 | A kind of Quercetin novel crystal forms and preparation method thereof |
| CN113185485B (en) | 2021-05-10 | 2022-03-04 | 合肥立方制药股份有限公司 | Semi-synthesis method of dihydroquercetin |
| CN113214210B (en) | 2021-05-10 | 2022-03-04 | 合肥立方制药股份有限公司 | Preparation method of dihydroquercetin |
| CN115944666A (en) * | 2022-12-27 | 2023-04-11 | 宁波杰顺生物科技有限公司 | Sophora flower bud extract and preparation method thereof |
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