CN113557234A - Semi-synthesis method of apigenin - Google Patents
Semi-synthesis method of apigenin Download PDFInfo
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- CN113557234A CN113557234A CN202080017053.8A CN202080017053A CN113557234A CN 113557234 A CN113557234 A CN 113557234A CN 202080017053 A CN202080017053 A CN 202080017053A CN 113557234 A CN113557234 A CN 113557234A
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- 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 title claims abstract description 63
- 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 title claims abstract description 61
- 229940117893 apigenin Drugs 0.000 title claims abstract description 61
- 235000008714 apigenin Nutrition 0.000 title claims abstract description 61
- 238000001308 synthesis method Methods 0.000 title claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 239000000243 solution Substances 0.000 claims abstract description 43
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000001914 filtration Methods 0.000 claims abstract description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- FTVWIRXFELQLPI-ZDUSSCGKSA-N (S)-naringenin Chemical compound C1=CC(O)=CC=C1[C@H]1OC2=CC(O)=CC(O)=C2C(=O)C1 FTVWIRXFELQLPI-ZDUSSCGKSA-N 0.000 claims abstract description 18
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims abstract description 18
- 239000000047 product Substances 0.000 claims abstract description 17
- WGEYAGZBLYNDFV-UHFFFAOYSA-N naringenin Natural products C1(=O)C2=C(O)C=C(O)C=C2OC(C1)C1=CC=C(CC1)O WGEYAGZBLYNDFV-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229940117954 naringenin Drugs 0.000 claims abstract description 14
- 235000007625 naringenin Nutrition 0.000 claims abstract description 14
- 239000000843 powder Substances 0.000 claims abstract description 14
- 239000012065 filter cake Substances 0.000 claims abstract description 11
- 239000003755 preservative agent Substances 0.000 claims abstract description 11
- 230000002335 preservative effect Effects 0.000 claims abstract description 11
- 239000007864 aqueous solution Substances 0.000 claims abstract description 10
- 239000000706 filtrate Substances 0.000 claims abstract description 10
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000013078 crystal Substances 0.000 claims abstract description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 7
- 239000011630 iodine Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 238000001556 precipitation Methods 0.000 claims description 8
- 239000000463 material Substances 0.000 claims 2
- 238000000034 method Methods 0.000 abstract description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 3
- 239000012670 alkaline solution Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 description 2
- 238000011085 pressure filtration Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 240000007087 Apium graveolens Species 0.000 description 1
- 235000015849 Apium graveolens Dulce Group Nutrition 0.000 description 1
- 235000010591 Appio Nutrition 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 244000175448 Citrus madurensis Species 0.000 description 1
- 241001672694 Citrus reticulata Species 0.000 description 1
- 235000017317 Fortunella Nutrition 0.000 description 1
- 241000234280 Liliaceae Species 0.000 description 1
- 229910004878 Na2S2O4 Inorganic materials 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 241000218641 Pinaceae Species 0.000 description 1
- 241000013557 Plantaginaceae Species 0.000 description 1
- 241000219050 Polygonaceae Species 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 240000001341 Reynoutria japonica Species 0.000 description 1
- 235000018167 Reynoutria japonica Nutrition 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 241001170744 Veratrum nigrum Species 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- -1 flavonoid compound Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000001052 yellow pigment Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/40—Separation, e.g. from natural material; Purification
Abstract
A semi-synthesis method of apigenin comprises the following steps: reacting naringenin and iodine at the temperature of 100-120 ℃ by using dimethyl sulfoxide as a solvent; adding sodium hydrosulfite or preservative powder and 25-50% of ethanol aqueous solution by volume fraction into the reaction solution, and reacting at 70-90 ℃ in an alkaline environment; filtering the reaction solution while the reaction solution is hot, collecting filtrate, adjusting the temperature to be 30-40 ℃ and the pH value to be 6-7, adding 50-80% ethanol water solution by volume fraction, filtering after crystals are separated out, collecting filter cakes, and obtaining the apigenin product. The method has the advantages of mild reaction conditions, easy control, simple steps, convenient operation, short time consumption, low cost, high yield and no pollution to the environment.
Description
Technical Field
The invention relates to the technical field of synthesis of pharmaceutical and chemical products, in particular to a semi-synthesis method for preparing apigenin.
Background
Apigenin, Apigenin and Apigenin, wherein the English name is Apigenin, the chemical name is 4, 5, 7-trihydroxyflavone, and the CAS number is 520-36-5, and the Apigenin is a flavonoid compound. It is widely distributed in nature, and mainly exists in vegetables, fruits, beans, tea leaves, and Scrophulariaceae plant such as Citrus reticulata Blanco, Polygonum cuspidatum of Polygonaceae, Liliaceae plant such as Veratrum nigrum and Pinaceae plant in warm and hot zone in the form of plant yellow pigment, wherein the content of celery is the highest. The pure apigenin is yellow powder, odorless, tasteless, hardly soluble in water, slightly soluble in hot alcohol, soluble in dilute alkali solution, and natural antioxidant.
Modern researches find that apigenin has various pharmacological effects, such as anti-tumor, anti-arteriosclerosis, antithrombotic, antiviral, antibacterial and anti-inflammatory, diuretic, tranquilizing, nerve soothing, blood pressure lowering, and Parkinson's disease resistance, wherein the anti-tumor effect is the most prominent, and the apigenin has inhibition effects on breast cancer, gastric cancer, prostate cancer, liver cancer, ovarian cancer and the like, so that the apigenin has high medicinal value.
In the traditional method for industrially producing apigenin, the traditional Chinese medicine extraction technology is adopted to extract and enrich the apigenin in natural plants, but due to the low content of the apigenin in the natural plants and the limitation of the traditional Chinese medicine extraction technology, the method has the defects of low extraction rate, high energy consumption and high cost, and is difficult to meet the increasing market demand. Therefore, a chemical synthesis method is commonly adopted at present, for example, chinese patent application CN1793137A discloses a semi-synthesis method of apigenin, which specifically uses naringenin as a raw material to react with iodine in a solvent of 1, 4-dioxane at a temperature of 50-130 ℃, and oxidative dehydrogenation is performed to generate a crude apigenin product, and the crude product is crystallized and recrystallized or purified by reflux to obtain refined apigenin. However, this method has the following disadvantages: 1. 1, 4-dioxane with high toxicity and high price is used as a solvent, so that environmental pollution is easily caused and the production cost is high; 2. the crude apigenin generated by oxidative dehydrogenation is obtained by concentration, water addition, standing and suction filtration, the crude product needs to be dissolved and crystallized by alkaline solution, and then recrystallized or refluxed by solvent, the steps are complex, and the time consumption is long; 3. the yield of the method is only 60-70%, and the method is relatively low and increases the production cost.
Technical problem
The invention aims to solve the technical problems of complex process, long time consumption, low yield, high cost and environmental pollution of the existing apigenin semi-synthesis method in the background art.
Technical solution
In order to achieve the above object, the present invention provides a semi-synthesis method of apigenin, comprising the steps of:
1) reacting naringenin and iodine at the temperature of 100-120 ℃ by using dimethyl sulfoxide as a solvent;
2) after the reaction in the step 1) is finished, adding sodium hydrosulfite or preservative powder and 25-50% of ethanol aqueous solution by volume fraction into the reaction solution, and reacting at the temperature of 70-90 ℃ in an alkaline environment;
3) after the reaction in the step 2) is finished, filtering the reaction solution while the reaction solution is hot, and collecting filtrate;
4) adjusting the temperature of the filtrate obtained in the step 3) to be 30-40 ℃ and the pH value to be 6-7, adding 50-80% by volume of ethanol aqueous solution, and waiting for crystal precipitation;
5) and (4) after the crystal precipitation in the step 4) is finished, filtering, and collecting a filter cake to obtain the apigenin product.
In the semi-synthesis method provided by the invention, the chemical name of the sodium hydrosulfite is sodium hydrosulfite and sodium hydrosulfite with the chemical formula of Na2S2O4The product is a white sand-shaped crystal or light yellow powder chemical product, has a melting point of 300 ℃ (decomposition), an ignition temperature of 250 ℃, is insoluble in ethanol, is soluble in sodium hydroxide solution, and has strong reducibility, and the product can react strongly with water and burn. The so-called preservative powder is a conventional substitute for sodium hydrosulfite, and is generally higher than sodium hydrosulfite in reducing property and stability.
Preferably, in step 1) of the semi-synthesis method provided by the invention, the reaction temperature is 105-110 ℃, and the conversion rate of raw materials is the highest and the reaction speed is the fastest at the temperature.
From the viewpoint of maximizing resource utilization and saving cost, the amount of the dimethyl sulfoxide used in the step 1) of the semi-synthesis method provided by the invention is preferably 5-10ml/g naringenin.
From the viewpoint of maximizing resource utilization and saving cost, preferably, in step 1) of the semi-synthesis method provided by the present invention, the amount of iodine added is 0.05 to 0.1 times of the weight of naringenin fed.
In step 2) of the semi-synthesis method provided by the invention, the 25-50% volume fraction of ethanol aqueous solution has the functions of quenching the previous reaction on one hand and promoting the sodium hydrosulfite or preservative powder to participate in the next reaction on the other hand.
In step 2) of the semi-synthesis method provided by the invention, an alkaline environment is an important guarantee for ensuring that the reaction can be smoothly carried out, and preferably, the pH value of the alkaline environment is 8-11, so that the sodium hydrosulfite/preservative powder can lose efficacy when the pH value is lower than the range, and the by-product can be increased when the pH value is higher than the range.
Preferably, in step 2) of the semi-synthesis method provided by the present invention, the alkaline environment is achieved by adding an alkaline solution to the reaction solution, wherein the alkaline solution includes, but is not limited to, sodium hydroxide solution, potassium hydroxide solution, lithium hydroxide solution, sodium bicarbonate solution and sodium carbonate solution.
Preferably, in step 2) of the semi-synthesis method provided by the present invention, the reaction temperature is 85 ℃, and the optimal reaction effect can be achieved at the temperature.
Preferably, in the step 2) of the semi-synthesis method provided by the invention, the addition amount of the sodium hydrosulfite or the preservative powder is 10-20% of the weight of the naringenin feed.
Preferably, in step 3) of the semi-synthesis method provided by the present invention, the temperature of the reaction solution during filtration is ensured to be 50 ℃ or higher, and filtration is difficult if the temperature is too low.
More preferably, in step 3) of the semi-synthesis method provided by the present invention, the temperature of the reaction solution during filtration is ensured to be 50-60 ℃.
Preferably, in step 4) of the above semi-synthesis method provided by the present invention, the pH of the filtrate obtained in step 3) is adjusted by adding glacial acetic acid or phosphoric acid.
Preferably, in step 4) of the semi-synthesis method provided by the invention, the ethanol aqueous solution is added dropwise at a speed of 70-140ml/min, so that apigenin crystals are rapidly separated out, and the separated crystals are large particles uniformly distributed, thereby facilitating subsequent filtration and separation.
The filtration in the semi-synthesis method provided by the invention refers to a process of separating solid and liquid in a solution by a physical method, and common filtration methods are all applicable to the method provided by the invention, and include normal pressure filtration, reduced pressure filtration, centrifugal filtration and the like.
Advantageous effects
Compared with the semi-synthesis method of apigenin disclosed in the Chinese patent application CN1793137A (hereinafter referred to as a comparison document), the method provided by the invention has the following advantages:
1. the high-content apigenin is synthesized by adopting a one-pot method, the raw materials in the whole process are cheap and easy to obtain, the reaction condition is mild, the control is easy, the steps are simple, the operation is convenient, and the consumed time is short;
2. dimethyl sulfoxide is used as a reaction solvent, so that the method is environment-friendly, economic and environment-friendly, meets the requirement of waste liquid recycling, achieves the aim of zero discharge of three wastes, and is more suitable for industrial mass production;
3. after the chemical synthesis reaction is finished, related impurities, byproducts and the like in the reaction liquid can be effectively removed by innovatively adding sodium hydrosulfite or preservative powder into the reaction liquid and carrying out high-temperature reaction in an alkaline environment, and then the apigenin refined product with the purity equivalent to that in the comparison document can be obtained only by one-time crystallization (recrystallization and three-time crystallization are not needed), the yield is up to more than 90%, and the yield is improved by more than 20% -30% compared with that in 60% -70% of the comparison document.
Modes for carrying out the invention
The present invention will be described in further detail with reference to specific examples, which are illustrative of the present invention and are not to be construed as being limited thereto.
The raw materials and reagents used in the following examples were all commercially available except for those specifically mentioned. Sodium hydrosulfite (sodium hydrosulfite) used in the following examples was purchased from Shanghai Aladdin Biotech Co., Ltd; the preservative powder was purchased from kumquat science ltd, guangzhou city.
Example 1
Adding 10g naringenin and 50ml dimethyl sulfoxide into a 250ml three-necked bottle, stirring, dissolving and clarifying; adding 1g elemental iodine, heating to 100 deg.C for reaction, and stopping the reaction by monitoring naringenin residue content of less than 10% by HPLC (HPLC detection method, Asahi C18 chromatographic column, mobile phase is 50% acetonitrile water solution). After the reaction is finished, cooling to 70 ℃, adding 10ml of 50% ethanol water solution, adjusting the pH to 9 by 10mol/L sodium hydroxide solution, adding 2g of sodium hydrosulfite, and reacting for 2 hours; filtering while the solution is hot, and washing a filter cake by using 5ml of dimethyl sulfoxide; mixing the filtrates, cooling to 30 ℃, adding 5ml of 6mol/L hydrochloric acid to adjust the pH of the reaction solution to 6-7, dropwise adding 150ml of 50% ethanol aqueous solution at the speed of 70ml/min, precipitating out a large amount of product, monitoring the apigenin precipitation amount by HPLC to be more than 90%, filtering to obtain a filter cake which is an apigenin refined product, and performing vacuum drying at 50 ℃ to obtain 9.1g of red-brown apigenin dried product powder; the product weight yield was 91.00%. Loss on drying was 2.33%; HPLC purity 97.62%; the apigenin obtained by the detection is subjected to content determination by taking the apigenin standard substance (marked content is 98%) of the Zhongzhong institute as a control, and the content is detected to be 95.23%.
Example 2
Adding 10g naringenin and 70ml dimethyl sulfoxide into a 250ml three-necked bottle, stirring, dissolving and clarifying; 0.5g of elemental iodine was added, the reaction was warmed to 120 ℃ and stopped by monitoring the naringenin residue content of the reaction raw material by HPLC to less than 10% (HPLC detection method: Asahi C18 column, mobile phase: 50% acetonitrile aqueous solution). After the reaction is finished, cooling to 85 ℃, adding 10ml of 25% ethanol water solution, adjusting the pH to 8 by 10mol/L potassium hydroxide solution, adding 1g of sodium hydrosulfite, and reacting for 2 hours; filtering while the solution is hot, and washing a filter cake by using 5ml of dimethyl sulfoxide; mixing the filtrates, cooling to 35 deg.C, adding 5ml glacial acetic acid to adjust pH to 6-7, dripping 150ml 80% ethanol water solution at 120ml/min speed to precipitate a large amount of apigenin, monitoring apigenin precipitation amount by HPLC to be greater than 90%, filtering to obtain refined apigenin cake, and vacuum drying at 50 deg.C to obtain light yellow apigenin dried product 9.52 g; the weight yield was 95.2%. Loss on drying was 2.13%; HPLC purity 98.31%; the apigenin obtained by the previous step is subjected to content measurement by taking the apigenin standard (marked content is 98%) of the Zhongzhong institute as a control, and the content is 96.84%.
Example 3
Adding 1kg of naringenin and 10L of dimethyl sulfoxide into a 50L glass reaction kettle, stirring, dissolving and clarifying; adding 50g of elemental iodine, heating to 105 deg.C for reaction, and stopping the reaction by monitoring naringenin residue content of less than 10% by HPLC (HPLC detection method: Asahi C18 column, mobile phase is 50% acetonitrile water solution). After the reaction is finished, cooling to 85 ℃, adding 1L of 40% ethanol aqueous solution, adjusting the pH to 11 by 10mol/L lithium hydroxide solution, adding 100g of sodium hydrosulfite, and reacting for 2 hours; filtering while the solution is hot, and washing a filter cake by using 500ml of dimethyl sulfoxide; mixing the filtrates, cooling to 40 deg.C, adding 500ml glacial acetic acid to adjust pH to 6-7, adding dropwise 15L 70% ethanol water solution at 140ml/min to precipitate a large amount of apigenin, monitoring apigenin precipitation amount by HPLC to be greater than 90%, filtering to obtain filter cake (refined apigenin product), and vacuum drying at 50 deg.C to obtain pale yellow apigenin dried product 923 g; the weight yield was 92.30%. Loss on drying of 1.53%; HPLC purity 98.46%; the apigenin obtained by the previous step is subjected to content measurement by taking the apigenin standard substance (marked content is 98%) of the Zhongzhong institute as a control, and the content is detected to be 97.64%.
Example 4
Adding 1kg of naringenin and 5L of dimethyl sulfoxide into a 50L glass reaction kettle, stirring, dissolving and clarifying; adding 50g of elemental iodine, heating to 110 deg.C for reaction, and stopping the reaction by monitoring naringenin residue content of less than 10% by HPLC (HPLC detection method: Asahi C18 column, mobile phase is 50% acetonitrile water solution). After the reaction is finished, cooling to 90 ℃, adding 1L of 30% ethanol water solution, adjusting the pH to 10 by 10mol/L sodium carbonate solution, adding 200g of preservative powder, and reacting for 1 h; filtering while the solution is hot, and washing a filter cake by using 500ml of dimethyl sulfoxide; mixing filtrates, cooling to 40 deg.C, adding 500ml sulfuric acid to adjust pH of reaction solution to 6-7, dripping 15L 50% ethanol water solution at 90ml/min to precipitate a large amount of apigenin, monitoring by HPLC to obtain apigenin solution with a precipitation amount greater than 90%, filtering, and pulping filter cake with 15L 60% ethanol water solution at 70 deg.C for 10 hr; filtering to obtain refined apigenin filter cake, and vacuum drying at 50 deg.C for 30 hr to obtain pale yellow apigenin dried product 937 g; the weight yield was 93.70%. Loss on drying is 1.79%; HPLC purity 98.69%; the apigenin obtained by the previous step is subjected to content measurement by taking the apigenin standard substance (marked content is 98%) of the Zhongzhong institute as a reference, and the content is detected to be 97.42%.
Claims (9)
1. A semi-synthesis method of apigenin is characterized by comprising the following steps:
1) reacting naringenin and iodine at the temperature of 100-120 ℃ by using dimethyl sulfoxide as a solvent;
2) after the reaction in the step 1) is finished, adding sodium hydrosulfite or preservative powder and 25-50% of ethanol aqueous solution by volume fraction into the reaction solution, and reacting at the temperature of 70-90 ℃ in an alkaline environment;
3) after the reaction in the step 2) is finished, filtering the reaction solution while the reaction solution is hot, and collecting filtrate;
4) adjusting the temperature of the filtrate obtained in the step 3) to be 30-40 ℃ and the pH value to be 6-7, adding 50-80% by volume of ethanol aqueous solution, and waiting for crystal precipitation;
5) and (4) after the crystal precipitation in the step 4) is finished, filtering, and collecting a filter cake to obtain the apigenin product.
2. The semi-synthesis method of apigenin according to claim 1, characterized in that: the temperature of the step 1) is 105-110 ℃.
3. The semi-synthesis method of apigenin according to claim 1, characterized in that: in the step 1), the dosage of the dimethyl sulfoxide is 5-10ml/g of the naringenin.
4. The semi-synthesis method of apigenin according to claim 1, characterized in that: in the step 1), the addition amount of the iodine is 0.05-0.1 time of the weight of the naringenin feeding material.
5. The semi-synthesis method of apigenin according to claim 1, characterized in that: in the step 2), the pH value of the alkaline environment is 8-11.
6. The semi-synthesis method of apigenin according to claim 1, characterized in that: the reaction temperature in step 2) was 85 ℃.
7. The semi-synthesis method of apigenin according to claim 1, characterized in that: in the step 2), the addition amount of the sodium hydrosulfite or the preservative powder is 10-20% of the weight of the naringenin feeding material.
8. The semi-synthesis method of apigenin according to claim 1, characterized in that: in the step 3), the temperature of the reaction solution during filtration is 50 ℃ or higher.
9. The semi-synthesis method of apigenin according to claim 1, characterized in that: in the step 4), the adding mode of the ethanol water solution is dripping at the speed of 70-140 ml/min.
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| US20040242907A1 (en) * | 2003-05-30 | 2004-12-02 | Unitech Pharmaceuticals, Inc. | Methods of synthesizing flavonoids and chalcones |
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| CN102079737A (en) * | 2010-12-31 | 2011-06-01 | 昆明理工大学 | Method for preparing apigenin |
| CN103772336A (en) * | 2014-02-23 | 2014-05-07 | 闻永举 | Semi-synthesis method of phenolic hydroxyl flavonoid compounds and iodine recycling method |
| CN104031016A (en) * | 2014-06-24 | 2014-09-10 | 陕西嘉禾植物化工有限责任公司 | Synthetic method of apigenin |
| CN105982885A (en) * | 2015-02-25 | 2016-10-05 | 上海中医药大学 | Application of bavachinin and analogs of bavachinin |
| CN111004199A (en) * | 2019-12-26 | 2020-04-14 | 陕西嘉禾药业有限公司 | Preparation method of apigenin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040242907A1 (en) * | 2003-05-30 | 2004-12-02 | Unitech Pharmaceuticals, Inc. | Methods of synthesizing flavonoids and chalcones |
| CN1793137A (en) * | 2005-12-31 | 2006-06-28 | 浙江大学 | Process for semi-synthesizing of apiolin |
| CN102079737A (en) * | 2010-12-31 | 2011-06-01 | 昆明理工大学 | Method for preparing apigenin |
| CN103772336A (en) * | 2014-02-23 | 2014-05-07 | 闻永举 | Semi-synthesis method of phenolic hydroxyl flavonoid compounds and iodine recycling method |
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