CN103772336B - Phenolic hydroxyl group flavone compound semisynthesis and iodine recovery method - Google Patents
Phenolic hydroxyl group flavone compound semisynthesis and iodine recovery method Download PDFInfo
- Publication number
- CN103772336B CN103772336B CN201410059636.3A CN201410059636A CN103772336B CN 103772336 B CN103772336 B CN 103772336B CN 201410059636 A CN201410059636 A CN 201410059636A CN 103772336 B CN103772336 B CN 103772336B
- Authority
- CN
- China
- Prior art keywords
- iodine
- pyridine
- hydroxyl group
- phenolic hydroxyl
- flavone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- -1 Phenolic hydroxyl group flavone compound Chemical class 0.000 title claims abstract description 60
- 239000011630 iodine Substances 0.000 title claims abstract description 60
- 229910052740 iodine Inorganic materials 0.000 title claims abstract description 60
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 title claims abstract description 59
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 title claims abstract description 48
- 229930003944 flavone Natural products 0.000 title claims abstract description 48
- 235000011949 flavones Nutrition 0.000 title claims abstract description 48
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 238000000034 method Methods 0.000 title claims abstract description 37
- 235000013824 polyphenols Nutrition 0.000 title claims abstract description 37
- 238000011084 recovery Methods 0.000 title abstract description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 85
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 52
- VUYDGVRIQRPHFX-UHFFFAOYSA-N hesperidin Natural products COc1cc(ccc1O)C2CC(=O)c3c(O)cc(OC4OC(COC5OC(O)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 VUYDGVRIQRPHFX-UHFFFAOYSA-N 0.000 claims abstract description 49
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 44
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 42
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 40
- 239000002904 solvent Substances 0.000 claims abstract description 36
- ZONYXWQDUYMKFB-UHFFFAOYSA-N SJ000286395 Natural products O1C2=CC=CC=C2C(=O)CC1C1=CC=CC=C1 ZONYXWQDUYMKFB-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229930003949 flavanone Natural products 0.000 claims abstract description 33
- 235000011981 flavanones Nutrition 0.000 claims abstract description 33
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000001100 (2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one Substances 0.000 claims abstract description 31
- QUQPHWDTPGMPEX-QJBIFVCTSA-N hesperidin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]4[C@@H]([C@H](O)[C@@H](O)[C@H](C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-QJBIFVCTSA-N 0.000 claims abstract description 26
- QUQPHWDTPGMPEX-UHFFFAOYSA-N Hesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(COC4C(C(O)C(O)C(C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-UHFFFAOYSA-N 0.000 claims abstract description 25
- QUQPHWDTPGMPEX-UTWYECKDSA-N aurantiamarin Natural products COc1ccc(cc1O)[C@H]1CC(=O)c2c(O)cc(O[C@@H]3O[C@H](CO[C@@H]4O[C@@H](C)[C@H](O)[C@@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)cc2O1 QUQPHWDTPGMPEX-UTWYECKDSA-N 0.000 claims abstract description 25
- APSNPMVGBGZYAJ-GLOOOPAXSA-N clematine Natural products COc1cc(ccc1O)[C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO[C@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@@H](O)[C@H](O)[C@H]4O)cc3O2 APSNPMVGBGZYAJ-GLOOOPAXSA-N 0.000 claims abstract description 25
- 229940025878 hesperidin Drugs 0.000 claims abstract description 25
- ARGKVCXINMKCAZ-UHFFFAOYSA-N neohesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(CO)O3)OC3C(C(O)C(O)C(C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 16
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910052782 aluminium Inorganic materials 0.000 claims abstract description 14
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000004411 aluminium Substances 0.000 claims abstract description 10
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 81
- 238000003756 stirring Methods 0.000 claims description 45
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- 239000000047 product Substances 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 19
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 150000001298 alcohols Chemical class 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 10
- KZNIFHPLKGYRTM-UHFFFAOYSA-N apigenin Chemical compound C1=CC(O)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C=C2O1 KZNIFHPLKGYRTM-UHFFFAOYSA-N 0.000 claims description 10
- DFPMSGMNTNDNHN-ZPHOTFPESA-N naringin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](OC=2C=C3O[C@@H](CC(=O)C3=C(O)C=2)C=2C=CC(O)=CC=2)O[C@H](CO)[C@@H](O)[C@@H]1O DFPMSGMNTNDNHN-ZPHOTFPESA-N 0.000 claims description 10
- 238000001556 precipitation Methods 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- 239000001606 7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one Substances 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- 235000008714 apigenin Nutrition 0.000 claims description 9
- XADJWCRESPGUTB-UHFFFAOYSA-N apigenin Natural products C1=CC(O)=CC=C1C1=CC(=O)C2=CC(O)=C(O)C=C2O1 XADJWCRESPGUTB-UHFFFAOYSA-N 0.000 claims description 9
- 229940117893 apigenin Drugs 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 229930019673 naringin Natural products 0.000 claims description 9
- 229940052490 naringin Drugs 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 7
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 229930182478 glucoside Natural products 0.000 claims description 5
- 150000008131 glucosides Chemical class 0.000 claims description 5
- 150000003222 pyridines Chemical class 0.000 claims description 5
- 239000001117 sulphuric acid Substances 0.000 claims description 5
- 235000011149 sulphuric acid Nutrition 0.000 claims description 5
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- RAFHNDRXYHOLSH-SFTVRKLSSA-N eriodictyol 7-O-beta-D-glucopyranoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C(C(=O)C[C@H](O2)C=3C=C(O)C(O)=CC=3)C2=C1 RAFHNDRXYHOLSH-SFTVRKLSSA-N 0.000 claims description 4
- 230000008595 infiltration Effects 0.000 claims description 4
- 238000001764 infiltration Methods 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 4
- 239000006228 supernatant Substances 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- WKUHPOMCLBLCOV-MIUGBVLSSA-N Diosmetin 7-O-beta-D-glucopyranoside Chemical compound C1=C(O)C(OC)=CC=C1C(OC1=C2)=CC(=O)C1=C(O)C=C2O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 WKUHPOMCLBLCOV-MIUGBVLSSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 235000011054 acetic acid Nutrition 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 235000015165 citric acid Nutrition 0.000 claims description 3
- ADSYMQORONDIDD-ZJHVPRRPSA-N hesperetin 7-O-beta-D-glucoside Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)=CC(O)=C2C(=O)C1 ADSYMQORONDIDD-ZJHVPRRPSA-N 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 3
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- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- BNGXYYYYKUGPPF-UHFFFAOYSA-M (3-methylphenyl)methyl-triphenylphosphanium;chloride Chemical compound [Cl-].CC1=CC=CC(C[P+](C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 BNGXYYYYKUGPPF-UHFFFAOYSA-M 0.000 claims description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 2
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- RAFHNDRXYHOLSH-UHFFFAOYSA-N Eriodictyol-7-beta-D-glucopyranosid Natural products OC1C(O)C(O)C(CO)OC1OC1=CC(O)=C(C(=O)CC(O2)C=3C=C(O)C(O)=CC=3)C2=C1 RAFHNDRXYHOLSH-UHFFFAOYSA-N 0.000 claims description 2
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- 230000008022 sublimation Effects 0.000 claims description 2
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- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 1
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- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 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 description 1
- 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 description 1
- 235000005493 rutin Nutrition 0.000 description 1
- 229960004555 rutoside Drugs 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 239000011265 semifinished product Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 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 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B7/00—Halogens; Halogen acids
- C01B7/13—Iodine; Hydrogen iodide
- C01B7/14—Iodine
-
- 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
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/06—Benzopyran radicals
- C07H17/065—Benzo[b]pyrans
- C07H17/07—Benzo[b]pyran-4-ones
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses phenolic hydroxyl group flavone compound semisynthesis and iodine recovery method, relate to two kinds of approach of A, B and iodine and reclaim, during in A approach, flavone is soluble in the pyridine-type solvents of ethylene glycol or glycerol, with iodine as dehydrogenating agent, Heating Dehydrogenation generate flavone.In B approach, flavanone or the flavone pyridine insoluble in alcohol, use trivalent aluminium and flavanone complexation, its complexation and dehydrogen substance dissolubility in alcohol is big, abolishes flavone in aluminium complex with phosphoric acid etc., and flavone is water insoluble, separates out, and filters, to obtain final product.The reagent dosages such as the present invention leads to method for there being phenolic hydroxyl group flavanone dehydrogenation to prepare flavone compound, pyridine are little, process simple, are suitable for industrialized production.Preparing as a example by diosmin by Hesperidin, compared with existing various documents and patent, in the present invention, the consumption of organic solvent such as pyridine is minimum, processing the simplest, yield is the highest, and (iodide can be by hydrogen peroxide oxidation in environmental protection, reclaiming simple, yield is higher), it is easy to industrialized production.
Description
Technical field
The present invention relates to phenolic hydroxyl group flavanone dehydrogenation and generate phenolic hydroxyl group flavone compound semisynthesis and iodine recovery method, its field belongs to chemical, medical.
Background technology
Flavanone kind composition containing phenolic hydroxyl group: due to natural flavanone kind composition, it it is the secondary metabolite of plant, molecule is generally squeezed into the labelling of enzyme, containing relatively polyphenol hydroxyl, being widely present in nature, its rich content, extraction process is simple, cheap such as 90% Hesperidin market price per kilogram about 150 yuan, 98% naringin market price per kilogram about 260 yuan.But flavanone kind composition pharmacological action is obvious not as flavone compound, its reason system flavone compound conjugated structure is better than flavanone kind composition, the former is good compared with the latter at antiinflammatory, antioxidation, anti-radical action, need to prepare apigenin etc. as Hesperidin needs to prepare diosmin, naringin or naringenin.
Bromine oxidation dehydrogenation and shortcoming: flavone compound is prepared in flavanone kind composition dehydrogenation, its preparation method has bromine oxidation and iodine oxidizing process.In bromine oxidation, without exposed phenolic hydroxyl group in flavanone molecule, can directly use bromine dehydrogenation, it is with low cost.If but had phenolic hydroxyl group, for avoiding bromo-reaction, its phenolic hydroxyl group then should first be protected, and such as methyl-etherified, acetylation, there is protection, dehydrogenation, deprotection in the method, causes step many, and yield is on the low side, causes cost high.
Iodine oxidizing process dehydrogenation and shortcoming: in iodine oxidizing process, be divided into NaI-DMSO (dimethyl sulfoxide) or I2-DMSO high-temperature oxidation and I2-pyridine equal solvent method.The former is suitable in flavanone molecule without exposed phenolic hydroxyl group, with 5,7,4'-trimethoxy naringenin dehydrogenations generate 5,7, explanation as a example by 4'-trimethoxy apigenin, in this method, DMSO doubles as solvent and oxidant, and DMSO is close at a temperature of boiling point, can be with iodine oxide ion to iodine molecule, and iodine can be yellow with dihydro
Ketone reacts so that it is dehydrogenation, generates flavone.Although iodine is expensive, but iodine consumption is little, and its cost is the cheapest.Containing the flavanone of phenolic hydroxyl group, at high temperature phenolic hydroxyl group is also had because of DMSO certain oxidation, destroys flavone parent nucleus, then can not use NaI-DMSO (dimethyl sulfoxide) or I2-DMSO high-temperature oxidation, can only make I2-pyridine equal solvent method, on the one hand, because of pyridine equal solvent can not iodine oxide ion to iodine molecule, therefore the large usage quantity of iodine, cause cost high.On the other hand the coplanarity of flavone compound is better than flavanone kind composition, causes flavone compound molecule and molecule to be easier to overlapping arrangement, forms crystallization, cause its dissolubility in water and organic solvent to diminish, it is easy to separates out.Therefore, flavanone kind composition dehydrogenation product is higher or thorough dehydrogenation, needs more organic solvent.At conventional organic solvent such as pyridine, DMSO, DMF, wherein the boiling point of DMSO is 189 DEG C, and the boiling point of DMF is 152 DEG C, and the two boiling point is higher, it is difficult to reclaims, usually used as single use, causes high expensive.Furthermore, flavone compound, as limited in apigenin, diosmetin dissolubility in DMSO, DMF, it to be made to dissolve, it is necessary to more DMSO, DMF.Pyridine boiling point is 115 DEG C, compares first two and can reclaim, but there is also problems: first pyridine has alkalescence, easily becomes salt, the hydrogen iodide the most also generated with dehydrogenation to become salt, become the pyridine after salt with the phenolic hydroxyl group in flavone molecule, and boiling point significantly increases.Additionally, due to the ring electron stream of pyridine annulus π, and flavone is because of the oxygen on phenolic hydroxyl group, there is the pi-conjugated effect of P-, cause the ring electron stream of phenyl ring band π in flavone, produce π π complexation, making pyridine be increased by active force, strengthen the difficulty that pyridine reclaims further, the pyridine response rate is the highest.As a example by diosmin is prepared in Hesperidin dehydrogenation, two kinds of forms of pyridiniujm and pyridine π flavone π complexing, its reaction equation is as follows.Another through recovered under reduced pressure, the yield of pyridine is only capable of reaching 70%, and unrecovered pyridine has significantly pollution to environment.Secondly the cacodorous abnormal smells from the patient of pyridine, during reclaiming, has certain infringement to the health of employee.
Phenolic hydroxyl group flavanone kind composition dehydrogenation example: for the flavanone kind composition containing phenolic hydroxyl group, because it is of a great variety, such as Hesperidin, naringin, hesperetin, naringenin etc., the dehydrogenation of each compound, all can enumerate several methods, enumerate difficulty one by one relatively big, preparing diosmin with Hesperidin is the representational explanation iodo-pyridine present situation to the flavanone containing phenolic hydroxyl group.Citrus crop is the big trade agricultural product in third place in the world that the whole world is only second to Semen Tritici aestivi, Semen Maydis, is also the big fruit of the first in the world.Before 1978, mandarine annual production is stable at about 300,000 tons, and yield increases the most year after year, and mandarine yield in 2009 exceedes with 25,000,000 tons and occupies world-class Brazil continuous decades.Containing Hesperidin in Citrus abundanter, as 2010 editions Chinese Pharmacopoeias one regulation Pericarpium Citri Reticulatae Viride must not be less than 5.0% containing Hesperidin, Pericarpium Citri Reticulatae must not be less than 3.5% containing Hesperidin.Major part peel of Citrus reticulata Blanco is wasted, only on a small quantity as Pericarpium Citri Reticulatae and extraction Hesperidin.Diosmin system Hesperidin dehydrogenation product, there is Citrin sample effect, the permeability of vascular fragility and exception can be reduced, again for preventing and treating the auxiliary treatment of hypertension and arteriosclerosis, for treating capillary fragility effect relatively rutin, Hesperidin is eager to excel, and is had the advantages that toxicity is low.For treating hemorrhoid, chronic venous insufficiency etc., about 4000 tons of the Year's consumption whole world, and also consumption is also increasing year by year.Due to diosmin in natural content relatively low, current its preparation method system Hesperidin under the effect of iodine dehydrogenation generate.Owing to diosmin is water insoluble and majority of organic solvent, therefore in Hesperidin prepares the technique of diosmin, as a example by pyridine, its consumption generally reach Hesperidin 5 times amount ([1] Gao Yongjin. strengthen intravenous tension medicine diosmin synthesis progress research [J]. China Chemical Industry trade, 2013, (7): 226；[2] Chen Zhiyu. diosmin synthesis technique analyze [J]. Chinese science and technology in length and breadth, 2011, (7): 315；[3] Li Yushan, Wang Jingan. the synthesis technique [J] of diosmin. laboratory research and exploration, 2010,29 (8): 39-41；[4] Zhang Guangyue, Zhang Qiang. the production method [P] of diosmin. China, CN101089009A, 2007.12.19).YANG edema etc. use Microwave-assisted firing method, with I2Catalyst is made, with K with NaI2CO3, the ethanol solution of NaOH and pyridine mixed solvent set up reaction system as action solvent, Hesperidin is taken off hydroformylation step and prepares diosmin.Though certain embodiments avoids high temperature and reaction dissolvent system uses the high boiling point toxic solvent such as pyridine, dimethyl sulfoxide in a large number, but use the organic solvents such as more methanol, ethanol and post processing is loaded down with trivial details, diosmin synthesis total recovery is below 90%, the most higher ([5] YANG edema of industrialization cost, Liu Maodong, Lei Guoping, Zhu Zhenyu. a kind of diosmin crude drug synthetic method [P] meeting EP7 version quality standard. China, CN102653549A, 2012.09.05).The production system of a kind of diosmin such as Jin Haixia, it is characterised in that include reacting recovery system, neutralize in filtration system, dissolving crude product filtration system, semi-finished product and filtration system, be pulverized and mixed system, iodine recovery system, methanol/ethanol recovery system.In course of reaction, using a large amount of organic solvent, and the organic solvent response rate is only capable of reaching 90%, environmental pollution is relatively big, and step is more, and its industrialization cost is the highest.([6] Jin Haixia, Yang Xiangnong, Zhao Jingsong, Wang Ping. the production system [P] of a kind of diosmin. China, CN202011848U, 2011.10.19).
By Hesperidin-I2The example of-pyridine dehydrogenation understands, at iodo-pyridine in phenolic hydroxyl group flavone certain embodiments, although condition is the gentleest, but it is big to there is pyridine consumption, it is difficult to reclaim, and post processing is complicated, and yield is on the low side, causes product cost higher, as diosmin is prepared in Hesperidin dehydrogenation.
Summary of the invention
By Given this, salt is become with pyridine and its derivatives according to the flavone compound containing phenolic hydroxyl group, at the different solubility of alcohol, design two kinds of approach of A, B: A approach is that flavone compound dissolubility in pyridine-type solvents is little, and dissolubility is big in pyridines and alcohols mixed solvent；B approach be flavone compound in pyridines, or pyridines is little with dissolubility in alcohols mixed solvent.Two kinds of approach of A, B, preferably solve the dehydrogenation containing phenolic hydroxyl group flavanone kind composition and there is pyridine consumption greatly, and post processing is loaded down with trivial details, the problem that product yield is relatively low.As a example by preparing diosmin such as Hesperidin, the method used by the present invention, compared with existing any document and patent, method pyridine consumption of the present invention is minimum, and post processing is the simplest, and yield is the highest, environmental protection, it is easy to industrialized production；Consumption of organic solvent is few, and iodine dissolubility in acid liquid is little, it is easy to reclaim, and the response rate is high, it is easy to industrialized production.Therefore product preparation cost is cheap.
(it is mainly suitable for aglycon in A approach, such as naringenin, hesperetin etc.): pyridine-type solvents, phenolic hydroxyl group flavanone kind composition, alcohols solvent, iodine mixes, stirring, 20 DEG C-180 DEG C reacting by heating a period of times, form uniform solution, TLC/HPLC/UV follow-up investigations, add a small amount of insurance phenol or product is rapidly joined in the aqueous alkali containing sodium hydrosulfite, after stirring and dissolving, it is rapidly added aqueous acid, and stir, airtight placement, precipitation flavone precipitates, (acid liquid directly adds hydrogen peroxide in filtration, separate out iodine precipitation), water washing filter cake is to no acidic, drain, then dry or dry, obtain flavone compound；
(it is mainly suitable for glycosides in B approach, such as Hesperidin etc.): add trivalent aluminium ion compound, it is rapidly added pyridine-type solvents, mixing (preventing the trivalent aluminium ion compound moisture absorption) rapidly, add phenolic hydroxyl group flavanone kind composition, alcohols solvent, iodine mixes, stirring, 20 DEG C-180 DEG C reacting by heating a period of times, form uniform solution, TLC/HPLC/UV follow-up investigations, product is rapidly joined in water, stirring and dissolving rapidly, it is rapidly added dealumination agent aqueous solution, quickly stir, airtight placement, precipitation flavone precipitates, (acid liquid directly adds hydrogen peroxide in filtration, separate out iodine precipitation), water washing filter cake, drain, with a small amount of 50% ethanol infiltration filter cake (washing flavone adsorbs a small amount of iodine), and wash, drain, then dry or dry, obtain flavone compound；
Iodine reclaims: filters acid liquid and directly adds hydrogen peroxide, airtight placement (prevents iodine from volatilizing), precipitation iodine precipitates, acid liquid airtight (preventing iodine from volatilizing) heating and thermal insulation (iodine tiny precipitation particles rapid aggregation), makes iodine be formed the most irregularly shaped, siphon supernatant (yellowish-brown) while hot, residue acid liquid filters, a small amount of water washing iodine filter cake, solids with methanol or the ethanol of iodine is dissolved, steaming methanol or ethanol, then closed sublimation i.e. obtains iodine.
Described in the present invention containing trivalent aluminium ion compound, refer mainly to aluminum chloride, alchlor, aluminium triiodide, aluminum sulfate, aluminum nitrate and aluminium alcoholates (aluminium methoxide, ethylene glycol aluminum, glycerol aluminum etc.) etc., it is with flavanone kind composition molar ratio 3:1-1:3, wherein preferred aluminum trichloride (anhydrous), its mole dosage is preferably equal with the mole of flavanone, mixed dissolution preferential with pyridine-type solvents.
Phenolic hydroxyl group flavanone kind composition described in the present invention, refer mainly to Hesperidin (CAS:520-26-3), hesperetin-7-O-glucoside (CAS:31712-49-9), hesperetin (CAS:520-33-2), naringin (CAS:10236-47-2), naringenin (CAS:480-41-1), eriodictyol-7-O-glucoside, eriodictyol (CAS:552-58-9) etc..
Alcohols solvent described in the present invention, refers mainly to methanol, dehydrated alcohol, propanol, isopropanol, ethylene glycol, 1,2-PD, 1,3-PD, glycerol, wherein preferred ethylene glycol and glycerol, and consumption does not limits；Preferably methanol, its volumetric usage is less than pyridine-type solvents volume (such as pyridine 10ml, methanol volume is preferably no more than 10ml).
Pyridine-type solvents described in the present invention, refer mainly to pyridine, 2-picoline, 3-picoline, 4-picoline, 5-picoline, 2,6-lutidines etc..
Dealumination agent described in the present invention, refer mainly to various acid and its esters, can be phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydrosulfite, sulphuric acid, hydrochloric acid, hydrobromic acid, acetic acid, oxalic acid, citric acid, tartaric acid etc., or any two kinds and use mixed above, wherein preferably phosphoric acid, its consumption and trivalent aluminium mol ratio are not less than 1:1.
Acid described in the present invention, refers mainly to various acid, including phosphoric acid, sulphuric acid, hydrochloric acid, hydrobromic acid, acetic acid, oxalic acid, citric acid, tartaric acid etc., or any two kinds of uses the most mixed above, wherein preferably phosphoric acid, hydrochloric acid, sulphuric acid.
Flavone described in the present invention, refer mainly to the flavone containing phenolic hydroxyl group, its representative compound: diosmin (CAS:520-27-4), Radix seu Folium Tosicodendri Delavayi glucoside (CAS:17306-46-6), diosmetin (CAS:520-34-3), diosmetin-7-O-glucoside (CAS:20126-59-4), luteolin (CAS:491-70-3), apigenin (CAS:520-36-5), apigenin β-D-7-O-glucoside (CAS:578-74-5).
In A approach, with dihydroxylic alcohols or trihydroxylic alcohol for dehydrogenation solvent, dehydrogenation effect to be got well: generates explanation as a example by Radix seu Folium Tosicodendri Delavayi glucoside by naringin dehydrogenation, when with methanol-pyridine-type solvents, its product is dehydrogenation product and the mixture of iodo product, when methanol usage is the fewest, and dehydrogenation product is the most, and iodo product is the fewest；When spent glycol-pyridine-type solvents or glycerol-pyridine-type solvents, obtain dehydrogenation product, illustrate that ethylene glycol or glycerol can be as solvents.If not spent glycol, glycerol etc., only using pyridine as solvent and plumper, then can separate out precipitation in a large number, as apigenin is prepared in naringenin dehydrogenation, and product is through repeatedly acid rinsing, in drying course, always has pyridine foul smell；
B approach utilize trivalent aluminium salt easily and flavanone kind composition complexation, its complex and dehydrogenation product are all readily dissolved in alcohol, through heating, form uniform liquid, there is not the inclusion phenomenon separating out flavone crystallization, therefore having pyridine consumption the fewest, this complex is easily decomposed, by dealumination agents such as phosphoric acid, salt and flavone compounds such as generating aluminum phosphate.Owing to flavone compound is water insoluble, can separate out, filter, to obtain final product；In B method, utilize methanol or polyhydric alcohol can dissolve flavanone kind composition, iodine, pyridine and its derivatives, also can be dissolved in polyhydric alcohol through the flavone compound generated with iodine dehydrogenation, adding acid and neutralize pyridine, flavone compound is water insoluble, separates out, filter, to obtain final product；
Once with aluminum trichloride (anhydrous) and hesperetin, naringenin complexation dehydrogenation, but due to dehydrogenation product aluminum chloride and diosmetin or aluminum chloride and apigenin complexation, its product is water insoluble, need to repeatedly process or recrystallization, could obtain preferable dealuminzation effect, its process is loaded down with trivial details, not as A method processes simple.
In the recovery method of iodine, it is relevant that iodine forms irregular solids and pyridine in acid liquid, ethylene glycol, glycerol, methanol usage, consumption of organic solvent is the most, form iodine solids speed the slowest, iodine solids is the fewest, therefore in iodine certain embodiments, the reagent dosages such as pyridine, ethylene glycol, glycerol, methanol to lack, when reactant can not form uniform solution, can be suitably added pyridine, ethylene glycol, glycerol, make reaction thorough, consumption of organic solvent is minimum, the iodine response rate is the highest, creates optimal benefit；Owing to iodine has volatility or sublimability, whole reaction should be airtight.Iodine is slightly soluble in water, and in heating process, the aggregation velocity of iodine is accelerated, and is conducive to mutually assembling forming solid, when not heating, forms the solid time longer.
In A approach, constituted mixed solvent with the monohydric alcohols such as methanol and pyridine-type solvents, when the volume of the monohydric alcohols such as methanol is more than pyridine-type solvents volume, then have iodo thing to generate.
Pyridine and its derivatives is necessary plumper: as a example by naringin, glycerol or ethylene glycol are as solvent, when with CaCO3As plumper, water-bath more than 40 DEG C, react, and release CO2Gas, mainly obtains iodo thing, and dehydrogen substance is inconspicuous；When using pyridine and its derivatives as plumper, main dehydrogen substance, iodo thing is inconspicuous, illustrate that pyridine-type solvents is necessary plumper using dihydroxylic alcohols or trihydroxylic alcohol as solvent.
The invention discloses the method that phenolic hydroxy group flavanone prepares flavone, especially 4=CO, 5-OH flavanone and trivalent aluminium complexation dehydrogenation in alcohol prepares flavone, phosphoric acid except the method for flavone aluminium complex, the fastly recovering of iodine, those skilled in the art can use for reference present disclosure, difference is contained phenolic hydroxyl group flavanone and is suitably modified technological parameter, the method that flavone is prepared in realization such as the adjustment kind of solvent, consumption, temperature etc..Special needs to be pointed out is, during flavone is prepared in the various flavanone kind composition dehydrogenations containing phenolic hydroxyl group, ethylene glycol or glycerol are as solvent, solubilization is played in trivalent aluminium and flavone complexation, phosphoric acid plays the arbitrary effect abolishing flavone with the complexing of aluminum, and they all will be considered included by the present invention.Method described herein, principle substantially can not suitably be changed departing from present disclosure, spirit and scope or change and combine by related personnel, realizes and applies the technology of the present invention.
Owing to relating to the flavanone compounds containing phenolic hydroxyl group, kind is more, Numerous.It is thus impossible to be illustrated each glycosides compound, but in order to be further appreciated by the present invention, carrying out classification declaration with two kinds of approach of A, B, embodiment is as follows:
A approach, product dissolubility in the dihydroxylic alcohols or trihydroxylic alcohol solution of pyridines is big, Al3+Complexation is not necessarily:
Embodiment 1
Take 95% hesperetin 5g in 250ml iodine flask, add 6ml pyridine, 20ml ethylene glycol and 4.2g iodine, stir evenly, 80 DEG C of confined reactions of water-bath (or condensing tube upper end adds the drying tube of calcium chloride).Every 1h stirs 1 time, in uniform shape liquid after 2h, continues confined reaction 6h.Take a policy powder 0.5g, stirs, and is poured into rapidly in 300ml 1.5%NaOH solution, after stirring and dissolving, adds hydrochloric acid and is adjusted to acidity, after airtight placement 30min, and sucking filtration, obtain acid liquid 1 (another device is deposited) and filter cake.Water washing filter cake is to no acidic, and filter cake dissolves with 50% ethanol aqueous alkali, is being adjusted to pH3-5 with hydrochloric acid, is filtering, filter cake a small amount of 50% washing with alcohol filter cake, 60 DEG C of drying, obtain diosmetin 4.62g, purity 96.2% after placing 3h.
Embodiment 2
Take 95% hesperetin 5g in 250ml iodine flask, add 2-picoline 6ml, 20ml glycerol and 4.2g iodine, stir evenly, 85 DEG C of confined reactions of water-bath (or condensing tube upper end adds the drying tube of calcium chloride), stir 1 time, in uniform shape liquid after 1h, continuing confined reaction 7h, take a policy powder 0.5g, stir, it is poured into rapidly in 300ml 1.5%NaOH solution, stirring and dissolving, is rapidly added phosphoric acid and is adjusted to acidity, stirring, after airtight 30min, sucking filtration, obtain acid liquid 2 (another device is deposited) and filter cake.Water washing filter cake, to no acidic, with a small amount of 50% washing with alcohol filter cake, 60 DEG C of drying, obtains diosmetin 4.68g, purity 96.5%.
Embodiment 3
Take 98% naringin 10g in 250ml iodine flask, add 2-picoline 5ml, 20ml glycerol and 4.3g iodine, stir evenly, 80 DEG C of confined reactions of water-bath (or condensing tube upper end adds the drying tube of calcium chloride), stir 1 time every 2h, in uniform shape liquid after 8h, take a policy powder 0.5g, stir, be poured into rapidly in 500ml aqueous solution, stirring and dissolving, add phosphoric acid and be adjusted to acidity, after airtight 5h, sucking filtration, obtain acid liquid 3 (another device is deposited) and filter cake.Water washing filter cake is to no acidic, and filter cake washs filter cake, 60 DEG C of drying with a small amount of 50% ethanol infiltration, obtains Radix seu Folium Tosicodendri Delavayi glucoside 8.89g, purity 98.9%.
Embodiment 4
Take 98% naringenin 5.0g in 250ml iodine flask, add pyridine 5ml, 20ml ethylene glycol and 4.7g iodine, stir evenly, 90 DEG C of confined reactions of water-bath (or condensing tube upper end adds the drying tube of calcium chloride), stirring, in uniform shape liquid after 1h, after reacting 6h again, it is poured into rapidly in 300ml 1.5%NaOH solution (containing 0.2% sodium hydrosulfite), stirs, add 20% sulphuric acid and be adjusted to acidity, stirring, after 30min, sucking filtration, obtain acid liquid 4 (another device is deposited) and filter cake., water washing filter cake is to no acidic, and filter cake washs filter cake, 60 DEG C of drying with a small amount of 50% ethanol infiltration, obtains apigenin 4.46g, purity 98.8%.
B approach, product dissolubility in the monohydric alcohol solution such as dihydroxylic alcohols, trihydroxylic alcohol or methanol of pyridine is little, needs trivalent aluminium complexation solubilising further:
Embodiment 5
Quickly weigh aluminum trichloride (anhydrous) 3.5g, it is rapidly added 16ml pyridine mixing (a large amount of white cigarette of emerging, release big calorimetric), add 92% Hesperidin 16.5g, add methanol 7ml, stirring, add methanol 8ml, iodine 6.8g, stirring, 80 DEG C of confined reactions of water-bath (or condensing tube upper end adds the drying tube of calcium chloride), stir 1 time every 2h, in uniform syrupy liq after 4h, after reacting 4h again, add 500ml warm water, stirring is to dissolving rapidly, it is rapidly added phosphoric acid 20ml, stirring rapidly, mix thoroughly, after airtight placement 30min, sucking filtration, and wash filter cake with 100ml water, obtain acid liquid 5 (to be made up of filtrate+cleaning mixture, another device is deposited) and filter cake.Being washed with water and wash filter cake to the most no acidic and drain, with 100ml 50% ethanol rinse filter cake, drain (50% ethanol is recyclable), paper using wraps, 60 DEG C of drying, obtains khaki diosmin 15.8g, purity 93.7%.
Embodiment 6
Quickly take aluminum trichloride (anhydrous) 7.0g, it is rapidly added 2-picoline 35ml, add methanol 10ml, add 92% Hesperidin 33g, iodine 13.5g, add methanol 15ml, after stirring 2min, 80 DEG C of confined reactions of water-bath (or condensing tube upper end adds the drying tube of calcium chloride), stir 1 time every 2h, in uniform syrupy liq after 4h, after reacting 4h again, add 1000ml warm water, stirring is to dissolving rapidly, it is rapidly added phosphatase 24 0ml, stirring rapidly, mix thoroughly, after airtight placement 60min, sucking filtration also washs filter cake with 300ml water, obtain acid liquid 6 (to be made up of filtrate+cleaning mixture, another device is deposited) and filter cake.It is washed with water and washs filter cake to the most no acidic and drain.With 200ml 50% ethanol rinse filter cake, draining, paper using wraps filter cake, 60 DEG C of drying, obtains khaki diosmin 32.1g, purity 93.5%.
Embodiment 7
Take aluminum trichloride (anhydrous) 3.5g, add 16ml pyridine, add Hesperidin 92%16.5g, add ethylene glycol 25ml, iodine 6.8g, 80 DEG C of confined reactions of water-bath (or condensing tube upper end adds the drying tube of calcium chloride), stir 1 time every 2h, in uniform syrupy liq after 4h, then after reacting 4h, add 500ml warm water, stirring is to dissolving rapidly, is rapidly added phosphoric acid 20ml, stirs rapidly, add water 500ml, mix thoroughly, airtight cool, sucking filtration, and wash filter cake with 200ml water, obtain acid liquid 7 and filter cake.Water washing filter cake is the most no acidic and drains.Again with 100ml 50% ethanol rinse filter cake, draining, paper using wraps filter cake, 60 DEG C of drying, obtains khaki diosmin 15.4g, purity 93.4%.
Embodiment 8
Take aluminum trichloride (anhydrous) 3.5g, add 16ml pyridine, add Hesperidin 92%16.5g, add glycerol 20ml, adding iodine 6.8g, stirring, water-bath 80 DEG C forms uniform liquid, confined reaction (or condensing tube upper end adds the drying tube of calcium chloride), stir 1 time every 2h, in uniform syrupy liq after 4h, then after reacting 4h, adding 500ml warm water, stirring is to dissolving rapidly, is rapidly added phosphoric acid 20ml, stirring, adds water 500ml, mixes thoroughly rapidly, airtight cool, sucking filtration, obtain acid liquid 8 and filter cake.Water washing filter cake is the most no acidic and drains.Again with 100ml 50% ethanol rinse filter cake, draining, paper using wraps filter cake, 60 DEG C of drying, obtains khaki diosmin 15.6g, purity 93.3%.
Embodiment 9
Take aluminum trichloride (anhydrous) 3.5g, after adding the mixing of 16ml pyridine, add 98% naringin 16.0g, add methanol 14ml, iodine 7.0g, 80 DEG C of confined reactions of water-bath (or condensing tube upper end adds the drying tube of calcium chloride).Stirring 1 time every 2h, in uniform syrupy liq after 4h, then complete dehydrogenation after reacting 4h, add 500ml warm water, stirring is to dissolving rapidly, is rapidly added phosphoric acid 20ml, stirs rapidly, add water 500ml, mixes thoroughly, after airtight placement 5h, and sucking filtration, obtain acid liquid 9.Water washing filter cake is the most no acidic and drains.Again with 100ml 50% ethanol rinse filter cake, draining, paper using wraps, 60 DEG C of drying, obtains faint yellow Radix seu Folium Tosicodendri Delavayi glucoside 14.7g, purity 98.2%.
Embodiment 10
Take acid liquid 5, it is placed in 500ml round-bottomed flask, add 30% hydrogen peroxide 20ml, after airtight placing response 30min, after 95 DEG C of sealed thermal insulating 5h of water-bath, take out, the supernatant 250ml of siphon yellow while hot, water 100ml is added again to round-bottomed flask, sucking filtration, a small amount of water washing round-bottomed flask (round-bottomed flask still has some a small amount of iodine), water washing liquor sucking filtration in the lump, wash 2-3 time, the iodine in filter and filter paper is dissolved with methanol, in round-bottomed flask, in gas bath 80 DEG C of airtight distillations in round-bottomed flask without methanol, after 150 DEG C of distillations in gas bath, obtain iodine 6.2g, this iodine can direct reuse.
Embodiment 11
Take acid liquid 6 to be placed in 2000ml round-bottomed flask, add 30% hydrogen peroxide 50ml, after airtight placing response 30min, after 95 DEG C of sealed thermal insulating 5h of water-bath, take out, siphon supernatant 250ml while hot, water 100ml is added again to round-bottomed flask, sucking filtration, a small amount of water washing round-bottomed flask (round-bottomed flask still has some a small amount of iodine), water washing liquor sucking filtration in the lump, wash 2-3 time, the iodine in filter and filter paper is dissolved with methanol, in round-bottomed flask, in gas bath 90 DEG C of airtight distillations in round-bottomed flask without ethanol, after 150 DEG C of distillations in gas bath, obtain iodine 12.3g, this iodine can direct reuse.
Claims (8)
1. phenolic hydroxyl group flavone compound semisynthesis, it is typically characterized by, and comprises the steps:
Add trivalent aluminium ion compound, be rapidly added pyridine-type solvents, mix rapidly, add phenolic hydroxyl group two
Hydrogen flavone compound, alcohols solvent, iodine mix, stirring, 20 DEG C of-180 DEG C of reacting by heating, are formed all
One solution, TLC/HPLC/UV follow-up investigations, product is rapidly joined in water, stirring is molten rapidly
Solve, be rapidly added dealumination agent aqueous solution, quickly stir, airtight placement, separate out phenolic hydroxyl group flavonoid
Compound precipitates, and filters and obtains filter cake and acid liquid, water washing filter cake, drains, with 50% ethanol infiltration filter
Cake, and wash, drain, then dry or dry, obtain phenolic hydroxyl group flavone compound；
Filtering the acid liquid obtained and directly add hydrogen peroxide, airtight placement, separate out iodine precipitation, acid liquid is airtight to be added
Heat insulation, makes the iodine precipitation of precipitation be formed the most irregularly shaped, the supernatant of siphon yellowish-brown while hot, residue
Acid liquid filters, water washing iodine filter cake, solids with methanol or the ethanol of the whole iodine obtained is dissolved, steams
Methanol or ethanol, then closed sublimation i.e. obtains iodine；
Described phenolic hydroxyl group flavanone kind composition be Hesperidin, hesperetin-7-O-glucoside, naringin or
Eriodictyol-7-O-glucoside；
Described alcohols solvent is methanol, isopropanol, ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol or the third three
Alcohol；
Described pyridine-type solvents is pyridine, 2-picoline, 3-picoline, 4-picoline, 5-first
Yl pyridines or 2,6-lutidines.
2. the method for claim 1, it is characterised in that described trivalent aluminium ion compound is tri-chlorination
Aluminum, alchlor, aluminium triiodide, aluminum sulfate, aluminum nitrate or aluminium alcoholates, itself and phenolic hydroxyl group flavanone
Compound molar ratio 3:1-1:3, described aluminium alcoholates is aluminium methoxide, ethylene glycol aluminum or glycerol aluminum.
3. method as claimed in claim 2, it is characterised in that described trivalent aluminium ion compound is anhydrous trichlorine
Changing aluminum, its mole dosage is equal with the mole of phenolic hydroxyl group flavanone kind composition.
4. the method for claim 1, it is characterised in that described alcohols solvent is ethylene glycol or glycerol,
Consumption does not limits.
5. the method for claim 1, it is characterised in that described alcohols solvent is methanol, methanol volume is used
Amount is less than pyridine-type solvents volume.
6. the method for claim 1, it is characterised in that described dealumination agent be phosphoric acid, sodium dihydrogen phosphate,
In disodium hydrogen phosphate, sodium hydrosulfite, sulphuric acid, hydrochloric acid, hydrobromic acid, acetic acid, oxalic acid, citric acid, tartaric acid
One or more.
7. method as claimed in claim 6, it is characterised in that described dealumination agent is phosphoric acid, its consumption and trivalent
Aluminum ions mol ratio is not less than 1:1.
8. the method for claim 1, it is characterised in that described phenolic hydroxyl group flavone compound is buchu department
Bright, Radix seu Folium Tosicodendri Delavayi glucoside, diosmetin-7-O-glucoside or apigenin β-D-7-O-glucoside.
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| CN103772336B (en) * | 2014-02-23 | 2016-08-31 | 闻永举 | Phenolic hydroxyl group flavone compound semisynthesis and iodine recovery method |
| CN104610244A (en) * | 2014-12-16 | 2015-05-13 | 李玉山 | Halogen cyclic regeneration technology applied to dehydrogenation and hydrolysis reaction |
| CN108752402B (en) * | 2018-04-26 | 2020-08-07 | 杭州泽邦科技有限公司 | Preparation method of high-purity diosmin |
| CN111004199A (en) * | 2019-12-26 | 2020-04-14 | 陕西嘉禾药业有限公司 | Preparation method of apigenin |
| CN111100104B (en) * | 2019-12-26 | 2022-04-01 | 陕西嘉禾药业有限公司 | Preparation method of diosmetin |
| CN113698440A (en) * | 2020-05-21 | 2021-11-26 | 西华大学 | Method for preparing diosmin by adopting continuous-flow microreactor |
| CN113557234B (en) * | 2020-06-19 | 2023-12-01 | 邦泰生物工程(深圳)有限公司 | Semi-synthesis method of apigenin |
| CN112843243A (en) * | 2021-01-27 | 2021-05-28 | 张才来 | Preparation method and application of diosmin derivative sustained-release preparation |
| CN112979603A (en) * | 2021-03-08 | 2021-06-18 | 宜宾西华大学研究院 | Continuous flow micro-channel synthesis process of flavonoid compound |
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| CN1793137A (en) * | 2005-12-31 | 2006-06-28 | 浙江大学 | Process for semi-synthesizing of apiolin |
| CN101089009A (en) * | 2006-06-16 | 2007-12-19 | 四川协力制药有限公司 | Diosmin producing process |
| WO2010092592A2 (en) * | 2009-02-11 | 2010-08-19 | Elder Pharmaceuticals Ltd. | Process for the preparation of diosmin |
| CN102070689A (en) * | 2011-01-25 | 2011-05-25 | 湖南圆通药业有限公司 | Method for producing diosmin |
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| CN1793137A (en) * | 2005-12-31 | 2006-06-28 | 浙江大学 | Process for semi-synthesizing of apiolin |
| CN101089009A (en) * | 2006-06-16 | 2007-12-19 | 四川协力制药有限公司 | Diosmin producing process |
| WO2010092592A2 (en) * | 2009-02-11 | 2010-08-19 | Elder Pharmaceuticals Ltd. | Process for the preparation of diosmin |
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