CN113557234B - Semi-synthesis method of apigenin - Google Patents
Semi-synthesis method of apigenin Download PDFInfo
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- CN113557234B CN113557234B CN202080017053.8A CN202080017053A CN113557234B CN 113557234 B CN113557234 B CN 113557234B CN 202080017053 A CN202080017053 A CN 202080017053A CN 113557234 B CN113557234 B CN 113557234B
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- naringenin
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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 58
- 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 56
- 229940117893 apigenin Drugs 0.000 title claims abstract description 56
- 235000008714 apigenin Nutrition 0.000 title claims abstract description 56
- 238000001308 synthesis method Methods 0.000 title description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 29
- 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 24
- 239000000047 product Substances 0.000 claims abstract description 22
- 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 19
- 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 18
- 229940117954 naringenin Drugs 0.000 claims abstract description 18
- 235000007625 naringenin Nutrition 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 17
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000000843 powder Substances 0.000 claims abstract description 14
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000012065 filter cake Substances 0.000 claims abstract description 10
- 239000000706 filtrate Substances 0.000 claims abstract description 10
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 10
- 239000011630 iodine Substances 0.000 claims abstract description 10
- 239000013078 crystal Substances 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 238000001556 precipitation Methods 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 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 7
- 239000002994 raw material Substances 0.000 description 7
- 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
- 239000000203 mixture Substances 0.000 description 6
- 239000000126 substance 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
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000007689 inspection Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 230000001376 precipitating effect Effects 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 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
- 238000004519 manufacturing process Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 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
- 239000003513 alkali Substances 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- -1 flavonoid compound Chemical class 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
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000002936 tranquilizing effect Effects 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
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- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 241000234280 Liliaceae Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism 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
- 235000011613 Pinus brutia Nutrition 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
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003276 anti-hypertensive 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
- 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
- 238000005516 engineering process Methods 0.000 description 1
- 229930003935 flavonoid Natural products 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
- 230000002401 inhibitory effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 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
- 230000001737 promoting effect Effects 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
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- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
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- 201000011549 stomach cancer Diseases 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- 235000013616 tea 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A method for semi-synthesizing apigenin, comprising: taking dimethyl sulfoxide as a solvent, and reacting naringenin with iodine at 100-120 ℃; adding sodium hydrosulfite or raw powder and 25-50% ethanol water solution into the reaction solution, and reacting at 70-90 ℃ in alkaline environment; filtering the reaction solution while the reaction solution is hot, collecting filtrate, adjusting the temperature to 30-40 ℃ and the pH value to 6-7, adding 50-80% ethanol water solution by volume fraction, filtering after crystals are separated out, and collecting filter cakes to obtain apigenin products. 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 chemical products, in particular to a method for preparing apigenin by semisynthesis.
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, is a flavonoid compound. It is widely distributed in nature, and mainly exists in the form of vegetable yellow pigment in warm tropical vegetables, fruits, beans, tea, radix et rhizoma Rhei of Scrophulariaceae, rhizoma Polygoni Cuspidati of Polygonaceae, rhizoma et radix Veratri of Liliaceae, and Pinaceae, wherein the content of herba Apii Graveolentis is highest. The pure apigenin is yellow powder in appearance, odorless and tasteless, is almost insoluble in water, slightly soluble in hot alcohol and soluble in dilute alkali solution, and is a natural antioxidant.
The modern researches show that apigenin has a plurality of pharmacological actions, namely anti-tumor, anti-arteriosclerosis, antithrombotic, antiviral, antibacterial, anti-inflammatory, diuretic, tranquilizing, tranquillizing, antihypertensive, anti-parkinsonism and the like, wherein the apigenin has the most prominent anti-tumor action, such as inhibiting effects on breast cancer, gastric cancer, prostatic cancer, liver cancer, ovarian cancer and the like, so that the apigenin has high medicinal value.
The traditional method for industrially producing apigenin adopts the traditional Chinese medicine extraction technology to extract and enrich apigenin in natural plants, but has the defects of low extraction rate, high energy consumption and high cost due to the low content of apigenin in natural plants and the limitation of the traditional Chinese medicine extraction technology, and is difficult to meet the increasing market demands. Therefore, a chemical synthesis method is generally adopted at present, for example, chinese patent application No. 1793137A discloses a semi-synthesis method of apigenin, which specifically uses naringenin as a raw material, and the naringenin reacts with iodine in 1, 4-dioxane at the temperature of 50-130 ℃, so as to generate coarse apigenin through oxidative dehydrogenation, and the coarse apigenin is subjected to crystallization, recrystallization or reflux purification 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 product generated by oxidative dehydrogenation is obtained by concentrating, adding water, standing and suction filtering, and the crude apigenin product is dissolved and crystallized by alkali liquor, then recrystallized or reflowed by solvent, and the steps are complicated and the time consumption is long; 3. the yield of the method is only 60% -70%, and the method is relatively low, so that the production cost is increased.
Technical problem
The invention aims to solve the technical problems of complex process, long time consumption, low yield, high cost and environmental pollution existing in the prior 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) Taking dimethyl sulfoxide as a solvent, and reacting naringenin with iodine at 100-120 ℃;
2) After the reaction of the step 1) is finished, adding sodium hydrosulfite or raw powder and an ethanol aqueous solution with the volume fraction of 25-50% into the reaction solution, and reacting at 70-90 ℃ in an alkaline environment;
3) After the reaction of the step 2) is finished, filtering the hot reaction solution, 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 an ethanol water solution with the volume fraction of 50-80%, and waiting for crystal precipitation;
5) And (3) after the crystal precipitation in the step (4) is finished, filtering, and collecting a filter cake to obtain the apigenin product.
In the semi-synthetic method provided by the invention, the chemical name of the sodium hydrosulfite is sodium hydrosulfite, the chemical formula of the sodium hydrosulfite is Na 2 S 2 O 4 The product is a white sandy 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 when being reacted with water and burnt. The so-called stock powder is a conventional substitute for sodium hydrosulfite, which is generally higher in terms of reducibility and stability than sodium hydrosulfite.
Preferably, in the step 1) of the semi-synthetic method provided by the invention, the reaction temperature is 105-110 ℃, the raw material conversion rate is highest at the temperature, and the reaction speed is highest.
In view of maximizing resource utilization and saving cost, preferably, in the step 1) of the semi-synthesis method provided by the invention, the dosage of dimethyl sulfoxide is 5-10ml/g naringenin.
In view of maximizing resource utilization and saving cost, preferably, in the step 1) of the semi-synthesis method provided by the invention, the adding amount of iodine is 0.05-0.1 times of the feeding weight of naringenin.
In the step 2) of the semi-synthesis method provided by the invention, the ethanol water solution with the volume fraction of 25% -50% has the effects of quenching the previous reaction on one hand and promoting the sodium hydrosulfite or the raw powder to participate in the next reaction on the other hand.
In the step 2) of the semi-synthetic method provided by the invention, the alkaline environment is an important guarantee for ensuring that the reaction can be smoothly carried out, preferably, the pH value of the alkaline environment is 8-11, when the pH value is lower than the range, the sodium hydrosulfite/raw powder is invalid, and when the pH value is higher than the range, the byproduct is increased.
Preferably, in step 2) of the above semi-synthesis method provided by the present invention, the alkaline environment is achieved by adding an alkaline solution to the reaction solution, the alkaline solution including, but not limited to, sodium hydroxide solution, potassium hydroxide solution, lithium hydroxide solution, sodium bicarbonate solution and sodium carbonate solution.
Preferably, in the step 2) of the semi-synthesis method provided by the 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 raw powder is 10-20% of the naringenin feeding weight.
Preferably, in the step 3) of the above semi-synthesis method provided by the present invention, the temperature of the reaction solution at the time of filtration should be ensured to be 50 ℃ or higher, and filtration is difficult if the temperature is too low.
More preferably, in the step 3) of the above semi-synthesis method provided by the present invention, the temperature at the time of filtering the reaction solution should be ensured to be 50 to 60 ℃.
Preferably, in the step 4) of the semi-synthesis method provided by the invention, the pH value of the filtrate obtained in the step 3) is adjusted by adding glacial acetic acid or phosphoric acid.
Preferably, in the 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 facilitated to be rapidly separated out, and the separated crystals are large particles which are uniformly distributed, so that the subsequent filtration and separation are facilitated.
The filtration in the semi-synthetic method provided by the invention is a process of separating solid and liquid in a solution by adopting a physical method, and common filtration methods are applicable to the method of the invention, including normal pressure filtration, reduced pressure filtration, centrifugal filtration and the like.
Advantageous effects
Compared with a semi-synthesis method of apigenin disclosed in Chinese invention patent application CN1793137A (hereinafter referred to as 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, and the whole process has the advantages of cheap and easily available raw materials, mild reaction conditions, easiness in control, simple steps, convenience in operation and short time consumption;
2. dimethyl sulfoxide is used as a reaction solvent, so that the method is environment-friendly, economical and environment-friendly, meets the requirement of waste liquid recycling, achieves the purpose of zero emission 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 raw powder into the reaction liquid and reacting at a high temperature in an alkaline environment, and the apigenin refined product with the purity equivalent to that in a comparison file can be obtained by only one-time crystallization (without recrystallization and three-time crystallization) in the follow-up process, and the yield is up to more than 90 percent, and is improved by more than 20 to 30 percent compared with the yield of 60 to 70 percent in the comparison file.
Embodiments of the invention
The present invention will be described in further detail with reference to the following examples, which are illustrative of the present invention and are not intended to limit the present invention thereto.
The materials and reagents used in the examples below were purchased from the market unless otherwise specified. The sodium hydrosulfite used in the examples below was purchased from Shanghai Ala Biochemical technologies Co., ltd; the guaranty source powder was purchased from guangzhou, jia run technology limited.
Example 1
10g naringenin and 50ml dimethyl sulfoxide are added into a 250ml three-mouth bottle, and the mixture is stirred, dissolved and clarified; 1g of elemental iodine is added, the temperature is raised to 100 ℃ for reaction, the reaction is stopped by monitoring the naringenin residual ratio of the reaction raw material to be lower than 10% through HPLC (the HPLC detection method is that the moon is C18 chromatographic column, and the mobile phase is 50% acetonitrile water solution). Cooling to 70 ℃ after the reaction is finished, adding 10ml of 50% ethanol water solution, adjusting the pH to 9 with 10mol/L sodium hydroxide solution, adding 2g of sodium hydrosulfite, and reacting for 2 hours; filtering while the mixture is hot, and washing a filter cake by using 5ml of dimethyl sulfoxide; mixing the filtrates, cooling to 30deg.C, adding 5ml of 6mol/L hydrochloric acid to adjust pH of the reaction solution to 6-7, dripping 150ml of 50% ethanol water solution at a speed of 70ml/min, precipitating the product in large amount, monitoring the precipitation amount of apigenin by HPLC to be more than 90%, filtering, and vacuum drying the filter cake at 50deg.C to obtain 9.1g of reddish brown apigenin dry product powder; the yield by weight of the product was 91.00%. Drying weight loss of 2.33%; HPLC purity 97.62%; the content of apigenin obtained by the method is measured by taking a standard apigenin product (marked content is 98%) of the Chinese inspection institute as a reference, and the content is measured to be 95.23%.
Example 2
10g naringenin and 70ml dimethyl sulfoxide are added into a 250ml three-mouth bottle, and the mixture is stirred, dissolved and clarified; 0.5g of elemental iodine is added, the temperature is raised to 120 ℃ for reaction, the naringenin residue ratio of the reaction raw material is monitored by HPLC to be lower than 10%, and the reaction can be stopped (the HPLC detection method is that the moon is C18 chromatographic column, and the mobile phase is 50% acetonitrile water solution). Cooling to 85 ℃ after the reaction is finished, adding 10ml of 25% ethanol water solution, adjusting the pH to 8 with 10mol/L potassium hydroxide solution, adding 1g of sodium hydrosulfite, and reacting for 2h; filtering while the mixture is hot, and washing a filter cake by using 5ml of dimethyl sulfoxide; mixing the filtrates, cooling to 35deg.C, adding 5ml glacial acetic acid to adjust pH of the reaction solution to 6-7, dripping 150ml 80% ethanol water solution at a speed of 120ml/min, precipitating to obtain a large amount of product, monitoring apigenin precipitation amount by HPLC to be more than 90%, filtering, and vacuum drying at 50deg.C to obtain light yellow apigenin 9.52g; the weight yield was 95.2%. Drying weight loss 2.13%; HPLC purity 98.31%; the content of apigenin obtained by the method is measured by taking a standard apigenin product (marked content 98%) of the Chinese inspection hospital as a reference, 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; 50g of elemental iodine is added, the temperature is raised to 105 ℃ for reaction, the reaction is stopped by monitoring the naringenin residual ratio of the reaction raw material to be lower than 10% through HPLC (the HPLC detection method is that the moon is C18 chromatographic column, and the mobile phase is 50% acetonitrile water solution). Cooling to 85 ℃ after the reaction is finished, adding 1L of 40% ethanol water solution, adjusting the pH to 11 with 10mol/L lithium hydroxide solution, adding 100g sodium hydrosulfite, and reacting for 2h; filtering while the mixture is hot, and washing a filter cake by using 500ml of dimethyl sulfoxide; mixing the filtrates, cooling to 40deg.C, adding 500ml glacial acetic acid to adjust pH of the reaction solution to 6-7, dripping 15L70% ethanol water solution at a speed of 140ml/min, precipitating to obtain a large amount of product, monitoring apigenin precipitation amount by HPLC to be more than 90%, filtering, and vacuum drying at 50deg.C to obtain light yellow apigenin dry product 923g; the weight yield was 92.30%. Loss on drying 1.53%; HPLC purity 98.46%; the content of apigenin obtained by the method is measured by taking a standard apigenin product (marked content is 98%) of the Chinese inspection institute as a reference, and the content is 97.64%.
Example 4
Adding 1kg of naringenin and 5L of dimethyl sulfoxide into a 50L glass reaction kettle, stirring, dissolving and clarifying; 50g of elemental iodine is added, the temperature is raised to 110 ℃ for reaction, the reaction is stopped by monitoring the naringenin residual ratio of the reaction raw material to be lower than 10% through HPLC (the HPLC detection method is carried out on a Xuexi C18 chromatographic column, and the mobile phase is 50% acetonitrile water solution). Cooling to 90 ℃ after the reaction is finished, adding 1L of 30% ethanol water solution, adjusting the pH to 10 by 10mol/L sodium carbonate solution, adding 200g of raw powder, and reacting for 1h; filtering while the mixture is hot, and washing a filter cake by using 500ml of dimethyl sulfoxide; mixing the filtrates, cooling to 40deg.C, adding 500ml sulfuric acid to adjust pH of the reaction solution to 6-7, dripping 15L 50% ethanol water solution at a speed of 90ml/min, precipitating the product in large amount, monitoring apigenin precipitation amount by HPLC to be more than 90%, filtering, pulping the filter cake with 15L60% ethanol water solution at 70deg.C for 10 hr; filtering, and vacuum drying the filter cake which is the refined apigenin product at 50 ℃ for 30 hours to obtain 937g of light yellow apigenin dry product; the weight yield was 93.70%. Drying weight loss of 1.79%; HPLC purity 98.69%; the content of apigenin obtained by the method is measured by taking a standard apigenin product (marked content is 98%) of the Chinese inspection institute as a reference, and the content is 97.42%.
Claims (9)
1. A method for semi-synthesis of apigenin, comprising the steps of:
1) Taking dimethyl sulfoxide as a solvent, and reacting naringenin with iodine at 100-120 ℃;
2) After the reaction of the step 1) is finished, adding sodium hydrosulfite or raw powder and an ethanol aqueous solution with the volume fraction of 25-50% into the reaction solution, and reacting at 70-90 ℃ in an alkaline environment;
3) After the reaction of the step 2) is finished, filtering the hot reaction solution, 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 an ethanol water solution with the volume fraction of 50-80%, and waiting for crystal precipitation;
5) And (3) after the crystal precipitation in the step (4) is finished, filtering, and collecting a filter cake to obtain the apigenin product.
2. The method for semisynthesis of apigenin according to claim 1, wherein: the temperature of the step 1) is 105-110 ℃.
3. The method for semisynthesis of apigenin according to claim 1, wherein: in the step 1), the dosage of the dimethyl sulfoxide is 5-10ml/g of naringenin.
4. The method for semisynthesis of apigenin according to claim 1, wherein: in the step 1), the adding amount of iodine is 0.05-0.1 time of the naringenin feeding weight.
5. The method for semisynthesis of apigenin according to claim 1, wherein: in the step 2), the pH value of the alkaline environment is 8-11.
6. The method for semisynthesis of apigenin according to claim 1, wherein: the reaction temperature of the step 2) is 85 ℃.
7. The method for semisynthesis of apigenin according to claim 1, wherein: in the step 2), the addition amount of the sodium hydrosulfite or the raw powder is 10-20% of the naringenin feeding weight.
8. The method for semisynthesis of apigenin according to claim 1, wherein: in the step 3), the temperature of the reaction liquid during filtration is 50 ℃ or higher.
9. The method for semisynthesis of apigenin according to claim 1, wherein: in the step 4), the ethanol aqueous solution is added dropwise at a rate of 70-140 ml/min.
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Publication number | Priority date | Publication date | Assignee | Title |
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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 |
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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CN1544427A (en) * | 2003-11-20 | 2004-11-10 | 黑龙江大学 | Luteolin semi-synthesis method |
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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 |
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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