CN116041302A - Method for preparing flavonoid compound containing hydroxyl substituent - Google Patents
Method for preparing flavonoid compound containing hydroxyl substituent Download PDFInfo
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- CN116041302A CN116041302A CN202211542643.XA CN202211542643A CN116041302A CN 116041302 A CN116041302 A CN 116041302A CN 202211542643 A CN202211542643 A CN 202211542643A CN 116041302 A CN116041302 A CN 116041302A
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- -1 flavonoid compound Chemical class 0.000 title claims abstract description 48
- 125000002887 hydroxy group Chemical group [H]O* 0.000 title claims abstract description 43
- 238000000034 method Methods 0.000 title claims abstract description 42
- 229930003935 flavonoid Natural products 0.000 title claims abstract description 40
- 235000017173 flavonoids Nutrition 0.000 title claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 125000006239 protecting group Chemical group 0.000 claims abstract description 27
- 239000002253 acid Substances 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 239000007787 solid Substances 0.000 claims description 26
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000000010 aprotic solvent Substances 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- 150000002215 flavonoids Chemical class 0.000 claims description 5
- 239000003586 protic polar solvent Substances 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- SAILTPCYIYNOEL-UHFFFAOYSA-N 2-bromo-1,3,2-benzodioxaborole Chemical compound C1=CC=C2OB(Br)OC2=C1 SAILTPCYIYNOEL-UHFFFAOYSA-N 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 229940071870 hydroiodic acid Drugs 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000002244 precipitate Substances 0.000 claims description 3
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910000510 noble metal Inorganic materials 0.000 abstract description 7
- 229910001385 heavy metal Inorganic materials 0.000 abstract description 6
- 229930003944 flavone Natural products 0.000 abstract description 3
- 235000011949 flavones Nutrition 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 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 abstract description 2
- 150000002212 flavone derivatives Chemical class 0.000 abstract description 2
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 21
- 239000000047 product Substances 0.000 description 16
- 230000005311 nuclear magnetism Effects 0.000 description 5
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- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 2
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
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- 239000001257 hydrogen Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 230000007514 neuronal growth Effects 0.000 description 2
- 230000006576 neuronal survival Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 235000013824 polyphenols Nutrition 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000013076 target substance Substances 0.000 description 2
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 description 1
- 102000005636 Cyclic AMP Response Element-Binding Protein Human genes 0.000 description 1
- 108010045171 Cyclic AMP Response Element-Binding Protein Proteins 0.000 description 1
- CITFYDYEWQIEPX-UHFFFAOYSA-N Flavanol Natural products O1C2=CC(OCC=C(C)C)=CC(O)=C2C(=O)C(O)C1C1=CC=C(O)C=C1 CITFYDYEWQIEPX-UHFFFAOYSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000002206 flavan-3-ols Chemical class 0.000 description 1
- 235000011987 flavanols Nutrition 0.000 description 1
- 150000002213 flavones Chemical class 0.000 description 1
- HVQAJTFOCKOKIN-UHFFFAOYSA-N flavonol Natural products O1C2=CC=CC=C2C(=O)C(O)=C1C1=CC=CC=C1 HVQAJTFOCKOKIN-UHFFFAOYSA-N 0.000 description 1
- 150000002216 flavonol derivatives Chemical class 0.000 description 1
- 235000011957 flavonols Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 235000009569 green tea Nutrition 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 description 1
- 150000002515 isoflavone derivatives Chemical class 0.000 description 1
- 235000008696 isoflavones Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000006993 memory improvement Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004031 neuronal differentiation Effects 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
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- 229930000044 secondary metabolite Natural products 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
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Images
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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a method for preparing flavonoid compounds containing hydroxyl substituent groups, which comprises the following steps: provided are compounds of formula (1), wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 And R is 10 At least one of them is OR, the others are H OR hydroxyl; and (3) reacting the compound shown in the formula (1) in the presence of acid and a solvent, and removing the protecting group R in the compound to obtain the flavonoid compound containing the hydroxyl substituent. The polyhydroxy flavone obtained by the method has high yield and high purity, and noble metals are not needed in the preparation process, so that heavy metal residues in the product are avoided, the reaction can be carried out under normal pressure, the operation is simple and safe, the implementation is easy, and the method is suitable for industrial production.
Description
Technical Field
The invention relates to the field of medicine. In particular, the invention relates to a method for preparing flavonoid compounds containing hydroxyl substituent groups.
Background
Flavonoids are important secondary metabolites of plants, have a basic skeleton of C6-C3-C6, exist in the form of aglycones and glycosides, and can also be classified as plant polyphenols, and are found in almost all parts of plants, including roots, heartwood, bark, leaves, fruits and flowers. At present, more than 6000 natural flavonoid compounds are separated and identified and are respectively derived from fruits, vegetables, grains, soybeans, green tea, flowers, herbal medicines, fermented products, brewed wine and the like. Flavonoids can be classified into 11 categories based on the differences in structure, including flavanols, dihydroxyflavonoids, anthocyans, flavonols, flavones, isoflavones, etc.
It has been found that flavonoids are able to promote neuronal survival and growth and improvement of memory by modulating some cascade signals within the cell (e.g. ERK/CREB, PI3K/Akt etc.), whereas neuronal differentiation, survival and growth are closely related to Brain-derived neurotrophic factors (Brain-derived Neurotrophic Factor, BDNF) widely distributed throughout the central nervous system. Therefore, the plant flavone can prevent, alleviate and treat various viral diseases and aging-related diseases, can enhance immunity, reduce cancer risk, and has antibacterial properties.
In the disclosed method for synthesizing flavonoids containing hydroxy substituents, palladium-carbon catalytic hydrogenation is generally used to remove the protecting groups. The method not only uses flammable and explosive gas hydrogen, and is usually needed to be carried out in a high-pressure environment, so that the method has environmental safety hidden danger, heavy metal residues are easy to exist, the safety hidden danger exists for the use of medicines, and meanwhile, the noble metal palladium has higher cost, so that the method has certain limitation. Therefore, a method for synthesizing flavonoid compounds containing hydroxyl substituent groups is needed to be developed, which is simpler and more convenient to operate, has low cost and is efficient.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art to at least some extent. Therefore, the invention provides a method for preparing the flavonoid compound containing the hydroxyl substituent, the flavonoid compound containing the hydroxyl substituent obtained by the method has high yield and high purity, noble metals are not needed in the preparation process, so that heavy metal residues in the product are avoided, the reaction can be carried out under normal pressure, the operation is simple and safe, the implementation is easy, and the method is suitable for industrial production.
The invention provides a method for preparing flavonoid compounds containing hydroxyl substituent groups. According to an embodiment of the invention, the method comprises: provided are compounds of formula (1), wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 And R is 10 At least one of them is OR, the others are H OR hydroxyl; and (3) reacting the compound shown in the formula (1) in the presence of acid and a solvent, and removing the protecting group R in the compound to obtain the flavonoid compound containing the hydroxyl substituent. In one embodiment, the hydroxy substituent-containing flavonoid compound is a compound of formula (2), wherein R 1 ’、R 2 ’、R 3 ’、R 4 ’、R 5 ’、R 6 ’、R 7 ’、R 8 ’、R 9 ' and R 10 At least one of the's is OH, the remainder being H;
according to the method provided by the embodiment of the invention, the inventor creatively discovers that the protective group R can be effectively removed under the acidic condition, and meanwhile, other groups can be prevented from reacting, so that the residual heavy metal in the product caused by removing the protective group by adopting the traditional noble metal can be avoided, and the obtained flavonoid compound containing the hydroxyl substituent is high in yield and purity. If other treatment conditions are adopted, on one hand, the phenomenon that the protecting group R cannot be effectively removed may exist, and on the other hand, other groups may react, for example, alkali treatment is adopted, so that more impurities in the product are caused, and the product quality is affected.
According to the embodiment of the invention, the above method for preparing the flavonoid compound containing the hydroxyl substituent can also have the following additional technical characteristics:
according to the embodiment of the invention, the flavonoid compound containing the hydroxyl substituent shown in the formula (2) contains 1-5 hydroxyl groups.
According to the embodiment of the invention, the flavonoid compound containing the hydroxyl substituent shown in the formula (2) contains 1-3 hydroxyl groups.
According to an embodiment of the present invention, the flavonoid compound having a hydroxyl substituent represented by formula (2) is selected from
According to an embodiment of the invention, the protecting group R is selected from one or more of benzyl, methyl, methoxymethyl, benzyloxymethyl and 4-methoxybenzyl.
According to an embodiment of the invention, the protecting group R is selected from benzyl.
According to an embodiment of the invention, the acid is selected from one or more of a protic acid and a lewis acid.
According to an embodiment of the present invention, the protic acid is selected from one or more of concentrated sulfuric acid, concentrated hydrochloric acid, hydrobromic acid, and hydroiodic acid; the Lewis acid is selected from one or more of boron tribromide, boron trichloride, anhydrous aluminum trichloride, boron trifluoride diethyl ether and catechol boron bromide.
According to an embodiment of the invention, the solvent is selected from a protic solvent or an aprotic solvent.
According to an embodiment of the present invention, the protic solvent is selected from one or both of acetic acid and trifluoroacetic acid; the aprotic solvent is selected from one or more of dichloromethane, chloroform, tetrahydrofuran and toluene.
According to an embodiment of the present invention, the molar ratio of the compound represented by formula (1) to the acid is 1:3 to 1:15, preferably 1:3 to 1:5.
According to an embodiment of the invention, the reaction is carried out at atmospheric pressure.
According to an embodiment of the invention, the temperature of the reaction is 50-100 ℃, preferably 70-90 ℃.
According to an embodiment of the invention, the reaction time is 6-24 hours, preferably 16-20 hours.
According to an embodiment of the invention, the method further comprises: filtering the reaction liquid containing the flavonoid compound containing the hydroxyl substituent group, collecting solids and washing the solids; and recrystallizing the washed solid, collecting the precipitate, filtering and drying.
According to an embodiment of the present invention, the recrystallization is performed using an organic solvent.
According to an embodiment of the present invention, the organic solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, acetonitrile and water.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
The foregoing and/or additional aspects and advantages of the invention will become apparent and may be better understood from the following description of embodiments taken in conjunction with the accompanying drawings in which:
FIG. 1 shows a nuclear magnetic resonance diagram according to one embodiment of the present invention.
Detailed Description
Embodiments of the present invention are described in detail below. The following examples are illustrative only and are not to be construed as limiting the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The invention provides a method for preparing flavonoid compounds containing hydroxyl substituent groups. According to an embodiment of the invention, the method comprises: provided are compounds of formula (1), wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 And R is 10 At least one of them is OR, the others are H OR hydroxyl; and (3) reacting the compound shown in the formula (1) in the presence of acid and a solvent, and removing the protecting group R in the compound to obtain the flavonoid compound containing the hydroxyl substituent. In one embodiment, the hydroxy substituent-containing flavonoid compound is a compound of formula (2), wherein R 1 ’、R 2 ’、R 3 ’、R 4 ’、R 5 ’、R 6 ’、R 7 ’、R 8 ’、R 9 ' and R 10 At least one of the's is OH, the remainder being H;
according to the method disclosed by the embodiment of the invention, the R group in the compound shown in the formula (1) is a protecting group, and the R group is removed and replaced by H under the action of acid and a solvent to obtain the compound shown in the formula (2). The inventor creatively discovers that the protective group R can be effectively removed under the acidic condition, and other groups can be prevented from reacting, so that the residual heavy metal in the product caused by removing the protective group by adopting the traditional noble metal can be avoided, and the obtained flavonoid compound containing the hydroxyl substituent has high yield and high purity. If other treatment conditions are adopted, on one hand, the phenomenon that the protecting group R cannot be effectively removed may exist, and on the other hand, other groups may react, for example, alkali treatment is adopted, so that more impurities in the product are caused, and the product quality is affected.
According to the embodiment of the invention, the flavonoid compound containing the hydroxyl substituent shown in the formula (2) contains 1-5 hydroxyl groups.
According to the embodiment of the invention, the flavonoid compound containing the hydroxyl substituent shown in the formula (2) contains 1-3 hydroxyl groups.
According to an embodiment of the present invention, the flavonoid compound having a hydroxyl substituent represented by formula (2) is selected from
According to an embodiment of the invention, the protecting group R is selected from one or more of benzyl, methyl, methoxymethyl, benzyloxymethyl and 4-methoxybenzyl. The groups can protect phenolic hydroxyl groups and avoid reaction. In some preferred embodiments, the protecting group R is selected from benzyl. Therefore, the method has better protection effect, is easy to remove under acidic conditions, and improves the yield, purity and preparation efficiency of the product.
According to an embodiment of the invention, the acid is selected from one or more of a protic acid and a lewis acid. Specifically, the proton acid is selected from one or more of concentrated sulfuric acid, concentrated hydrochloric acid, hydrobromic acid and hydroiodic acid, and the Lewis acid is selected from one or more of boron tribromide, boron trichloride, anhydrous aluminum trichloride, boron trifluoride diethyl ether and catechol boron bromide. Thus, the protecting group R can be effectively removed without affecting other groups.
According to an embodiment of the invention, the solvent is selected from a protic solvent or an aprotic solvent. More specifically, the aprotic solvent is selected from one or two of acetic acid and trifluoroacetic acid, and the aprotic solvent is selected from one or more of dichloromethane, chloroform, tetrahydrofuran and toluene. Thereby contributing to the reaction. Among them, acetic acid is excellent in effect.
According to an embodiment of the present invention, the molar ratio of the compound represented by formula (1) to the acid is 1:3 to 1:15. The inventor obtains the better proportion through a large number of experiments, so that the reaction can fully occur, all protecting groups are removed, the material waste is reduced, the treatment difficulty is reduced, and the method is environment-friendly. Preferably, the molar ratio of the compound of formula (1) to the acid is 1:3 to 1:7, and specifically, may be 1:3 to 1:5, 1:4 to 1:5, 1:5 to 1:7.
According to an embodiment of the invention, the reaction is carried out at atmospheric pressure. The inventor finds that the reaction of removing the protecting group under the acidic condition can be carried out under normal pressure, and the method is simple, convenient and safe to operate, easy to implement and beneficial to industrial amplification.
According to an embodiment of the invention, the temperature of the reaction is 50-100 ℃. Thus, the protecting group can be effectively removed. Specifically, the reaction temperature may be 50 to 60 ℃, 55 to 70 ℃, 75 to 85 ℃, 70 to 90 ℃, preferably 70 to 90 ℃.
According to an embodiment of the invention, the reaction time is 6-24 hours. Thus, the protecting group can be effectively removed. Specifically, the reaction time is 6 to 8 hours, 10 to 13 hours, 15 to 18 hours or 17 to 19 hours, preferably 16 to 20 hours.
According to an embodiment of the invention, the method further comprises: filtering the reaction solution containing the flavonoid compound containing the hydroxyl substituent group shown in the formula (2) obtained by the reaction, collecting solids, and washing the solids; the washed solid was recrystallized, and the precipitate was collected, filtered and dried. Thereby, in order to further improve the product purity.
According to an embodiment of the present invention, the recrystallization is performed using an organic solvent. Thus, the flavonoid compound containing hydroxyl substituent shown in the formula (2) is beneficial to crystallization. Specifically, the organic solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, acetonitrile and water.
In a specific embodiment, the method of the invention comprises the steps of: adding a compound shown in a formula (1) with a protecting group R and an acid into an organic solvent at room temperature and normal pressure, and after the temperature rising and stirring reaction is finished, filtering, washing and recrystallizing to obtain a purified product of the flavonoid compound containing the hydroxyl substituent shown in the formula (2). Further, the protecting group R is benzyl. Still further, the acid is concentrated sulfuric acid having a molar ratio of 4:1 to the compound of formula (1) having the protecting group R. Still further, the organic solvent is acetic acid. Still further, the reaction temperature was 80 ℃. Still further, the reaction time was 18 hours. Still further, the recrystallization uses a combination of methanol, acetonitrile and tetrahydrofuran in a volume ratio of 10:2:1.
Compared with the prior art, the invention provides a method for preparing flavonoid compounds containing hydroxyl substituent groups, which has one or more of the following advantages: 1) Compared with the prior art, the invention does not need noble metals such as palladium carbon, thereby avoiding the risk of residual heavy metals in the product; 2) The method can be carried out without using flammable and explosive hydrogen as a reagent for removing the protecting group and without high-pressure environment, so that the method is simple and safe to operate, easy to implement and beneficial to industrial amplification; 3) Compared with noble metals, the reagent used is commercial, is cheap and easy to obtain, is beneficial to controlling the production cost and is convenient for the industrial production of products.
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1
5.22kg of two benzyl-protected 7, 8-dihydroxyflavones were weighed and placed in a 100L reaction kettle. While stirring at room temperature, 59L of acetic acid and 2.62L of concentrated sulfuric acid (molar ratio of the compound represented by formula (1) to concentrated sulfuric acid: 1:4) were added, and then the temperature was raised to 80 ℃. After stirring the reaction for 18 hours, the reaction solution was cooled to room temperature and then directly filtered. The solid obtained was washed with 24L of water, recrystallized from a methanol, acetonitrile and tetrahydrofuran system (volume ratio 10:2:1), filtered and dried to give 2.78kg of a yellowish green solid with a yield of 91% and a purity of 99.7%.
1 H NMR(400MHz,DMSO-d 6 ) δ10.35 (s, 1H), 9.50 (s, 1H), 8.17-8.10 (m, 2H), 7.59-7.51 (m, 3H), 7.44 (d, j=8.6 hz, 1H), 6.98 (d, j=8.7 hz, 1H), 6.89 (s, 1H), see in particular fig. 1.
Example 2
4.12kg of a benzyl-protected 7, 8-dihydroxyflavone was weighed and placed in a 100L reaction vessel. While stirring at room temperature, 59L of acetic acid and 2.62L of concentrated sulfuric acid (molar ratio of the compound represented by formula (1) to concentrated sulfuric acid: 1:4) were added, and then the temperature was raised to 75 ℃. After stirring the reaction for 18.5 hours, the reaction solution was cooled to room temperature and then directly filtered. The solid obtained was washed with 24L of water, recrystallized from a system of methanol, acetonitrile and tetrahydrofuran (volume ratio 10:2:1), filtered and dried to give 2.78kg of a yellowish green solid, yield 91%, purity 99.5%, verified by nuclear magnetism as the target substance.
Example 3
3.38kg of two methyl-protected 7, 8-dihydroxyflavones were weighed and placed in a 100L reaction kettle. While stirring at room temperature, 59L of acetic acid and 2.62L of concentrated sulfuric acid (molar ratio of the compound represented by formula (1) to concentrated sulfuric acid: 1:4) were added, and then the temperature was raised to 82 ℃. After stirring the reaction for 17 hours, the reaction solution was cooled to room temperature and then directly filtered. The solid obtained was washed with 24L of water, recrystallized from a system of methanol, acetonitrile and tetrahydrofuran (volume ratio 10:2:1), filtered and dried to give 2.74kg of a yellowish green solid, yield 90%, purity 99.5%, verified by nuclear magnetism as the target.
Example 4
5.22kg of two benzyl-protected 7, 8-dihydroxyflavones were weighed and placed in a 100L reaction kettle. While stirring at room temperature, 59L of acetic acid and 5.9L of concentrated hydrochloric acid (molar ratio of the compound represented by formula (1) to concentrated hydrochloric acid: 1:6) were added, and then the temperature was raised to 80 ℃. After stirring the reaction for 19 hours, the reaction solution was cooled to room temperature and then directly filtered. The solid obtained was washed with 24L of water, recrystallized from a system of methanol, acetonitrile and tetrahydrofuran (volume ratio 10:2:1), filtered and dried to give 2.78kg of a yellowish green solid, yield 91%, purity 99.3%, verified by nuclear magnetism as the target substance.
Example 5
46.02g of benzyl-protected 7-hydroxyflavone are weighed and placed in a 1L reaction kettle. 500mL of acetic acid and 30.7mL of concentrated sulfuric acid (molar ratio of the compound represented by formula (1) to concentrated sulfuric acid: 1:4) were added while stirring at room temperature, and then the temperature was raised to 88 ℃. After stirring the reaction for 16.5 hours, the reaction solution was cooled to room temperature and then directly filtered. The resulting solid was washed with 300mL of water, recrystallized from a methanol, acetonitrile and tetrahydrofuran system (volume ratio 10:2:1), filtered and dried to give 30.38g of a yellow solid in 91% yield and 99.7% purity.
1 H NMR(400MHz,DMSO-d 6 )δ10.88(s,1H),8.15–7.99(m,2H),7.90(d,J＝8.7Hz,1H),7.63–7.50(m,3H),7.01(d,J＝2.3Hz,1H),6.94(dd,J＝8.7,2.3Hz,1H),6.89(s,1H).
Example 6
3.38kg of two methyl-protected 7, 8-dihydroxyflavones were weighed and placed in a 100L reaction kettle. While stirring at room temperature, 59L of methylene chloride and 12kg of boron tribromide (the molar ratio of the compound represented by formula (1) to boron tribromide: 1:4) were added, and the temperature was then raised to 80 ℃. After stirring the reaction for 18 hours, the reaction solution was cooled to room temperature and then directly filtered. The solid obtained was washed with 24L of water, recrystallized from a system of methanol, acetonitrile and tetrahydrofuran (volume ratio 10:2:1), filtered and dried to give 2.74kg of a yellowish green solid, yield 90%, purity 99.0%, verified by nuclear magnetism as the target.
Example 7
4.10kg of two methoxymethyl-protected 7, 8-dihydroxyflavones were weighed and placed in a 100L reaction kettle. 3.66L of trifluoroacetic acid (molar ratio of the compound represented by formula (1) to trifluoroacetic acid: 1:4) was added while stirring at room temperature, and then the temperature was raised to 80 ℃. After stirring for 18 hours, the reaction solution was cooled to room temperature, 24L of water was added, and then filtration was carried out, and after recrystallization with a system of methanol, acetonitrile and tetrahydrofuran (volume ratio: 10:2:1), filtration and drying gave 2.67kg of a yellowish green solid, 60% yield, 89% purity, and nuclear magnetism was confirmed as the objective.
Example 8
5.22kg of two benzyl-protected 7, 8-dihydroxyflavones were weighed and placed in a 100L reaction kettle. While stirring at room temperature, 59L of acetic acid and 1L of concentrated sulfuric acid (the molar ratio of the compound represented by formula (1) to concentrated sulfuric acid is 1:1.5) were added, and then the temperature was raised to 80 ℃. After stirring the reaction for 18 hours, the reaction solution was cooled to room temperature and then directly filtered. The solid obtained was washed with 24L of water, recrystallized from a methanol, acetonitrile and tetrahydrofuran system (volume ratio 10:2:1), filtered and dried to give 1.6kg of a yellowish green solid with a yield of 52% and a purity of 90%.
Example 9
5.22kg of two benzyl-protected 7, 8-dihydroxyflavones were weighed and placed in a 100L reaction kettle. While stirring at room temperature, 59L of acetic acid and 2.62L of concentrated sulfuric acid (molar ratio of the compound represented by formula (1) to concentrated sulfuric acid: 1:4) were added, and then the temperature was raised to 40 ℃. After stirring for 18 hours, the reaction mixture was cooled to room temperature, and no deprotection reaction occurred.
Example 10
5.22kg of two benzyl-protected 7, 8-dihydroxyflavones were weighed and placed in a 100L reaction kettle. While stirring at room temperature, 59L of acetic acid and 2.62L of concentrated sulfuric acid (molar ratio of the compound represented by formula (1) to concentrated sulfuric acid: 1:4) were added, and then the temperature was raised to 80 ℃. After stirring the reaction for 4 hours, the reaction solution was cooled to room temperature and then directly filtered. The resulting solid was washed with 24L of water, recrystallized from a methanol, acetonitrile and tetrahydrofuran system (volume ratio 10:2:1), filtered and dried to give 1.16kg of a yellowish green solid in a yield of 38% and purity of 44%.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (10)
1. A process for preparing a hydroxy-substituted flavonoid comprising:
provided are compounds of formula (1), wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 And R is 10 At least one of them is OR, the others are H OR hydroxyl;
reacting the compound shown in the formula (1) in the presence of acid and solvent, removing the protecting group R in the compound to obtain the flavonoid compound containing hydroxyl substituent,
2. the method according to claim 1, wherein the flavonoid compound having a hydroxyl group is a compound represented by the formula (2), wherein R 1 ’、R 2 ’、R 3 ’、R 4 ’、R 5 ’、R 6 ’、R 7 ’、R 8 ’、R 9 ' and R 10 At least one of the's is OH, the remainder being H;
3. the method according to claim 2, wherein the flavonoid compound containing a hydroxyl substituent represented by the formula (2) contains 1 to 5 hydroxyl groups;
optionally, the flavonoid compound containing hydroxyl substituent shown in the formula (2) contains 1-3 hydroxyl groups;
preferably, the flavonoid compound containing hydroxyl substituent shown in the formula (2) is selected from
4. A method according to any one of claims 1 to 3, wherein the protecting group R is selected from one or more of benzyl, methyl, methoxymethyl, benzyloxymethyl and 4-methoxybenzyl;
preferably, the protecting group R is selected from benzyl.
5. The method of any one of claims 1-4, wherein the acid is selected from one or more of a protic acid or a lewis acid;
preferably, the protic acid is selected from one or more of concentrated sulfuric acid, concentrated hydrochloric acid, hydrobromic acid and hydroiodic acid;
preferably, the lewis acid is selected from one or more of boron tribromide, boron trichloride, anhydrous aluminum trichloride, boron trifluoride etherate, and catechol boron bromide.
6. The method according to any one of claims 1 to 5, wherein the solvent is selected from the group consisting of a protic solvent or an aprotic solvent;
preferably, the protic solvent is selected from one or both of acetic acid and trifluoroacetic acid;
preferably, the aprotic solvent is selected from one or more of dichloromethane, chloroform, tetrahydrofuran and toluene.
7. The method according to any one of claims 1 to 6, wherein the molar ratio of the compound of formula (1) to the acid is 1:3 to 1:15, preferably 1:3 to 1:7.
8. The process according to any one of claims 1 to 7, wherein the reaction is carried out at atmospheric pressure; and/or
The temperature of the reaction is 50-100 ℃, preferably 70-90 ℃; optionally, the reaction time is from 6 to 24 hours, preferably from 16 to 20 hours.
9. The method according to any one of claims 1-8, wherein the method further comprises:
filtering the reaction liquid containing the flavonoid compound containing the hydroxyl substituent group, collecting solids and washing the solids; and
the washed solid was recrystallized, and the precipitate was collected, filtered and dried.
10. The method according to claim 9, wherein the recrystallization is performed using an organic solvent;
preferably, the organic solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, acetonitrile and water.
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| CN102079737A (en) * | 2010-12-31 | 2011-06-01 | 昆明理工大学 | Method for preparing apigenin |
| CN104926768A (en) * | 2014-03-21 | 2015-09-23 | 景临林 | Moslosooflavone, isowogonin and norwogonin synthetic method |
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