CN103145670A - Semisynthesis luteolin preparation new process - Google Patents
Semisynthesis luteolin preparation new process Download PDFInfo
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- CN103145670A CN103145670A CN2013100213253A CN201310021325A CN103145670A CN 103145670 A CN103145670 A CN 103145670A CN 2013100213253 A CN2013100213253 A CN 2013100213253A CN 201310021325 A CN201310021325 A CN 201310021325A CN 103145670 A CN103145670 A CN 103145670A
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Abstract
The invention provides semisynthesis luteolin preparation new process. The process includes a first step of hydrolyzing hesperidin to obtain hesperetin, a second step of demethylating the hesperetin to obtain eriodictyol, and a third step of dehydrogenizing the eriodictyol to obtain the luteolin. Compared with the prior art that the hesperidin is firstly dehydrogenized and then hydrolyzed, the process enables the iodine using amount to be greatly reduced, and production cost is low. The invention further provides technology for preparing the eriodictyol.
Description
Technical field
The present invention relates to a kind of novel process of semi-synthetic preparation luteolin.
Background technology
Luteolin at nature because being to isolate leaf, stem, the branch from Resedaceae (Resedaceae) Reseda herbaceous plant Reseda odorata (ResedaodorataL.) to gain the name at first.Mainly from the shell of leguminous plants Semen arachidis hypogaeae (Arachis hypogata L.) fruit, labiate Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.) (Ajuga decumbens Thunb.), gentianaceae plant Shi Sheng pivot holds (Gentianopsis palucisa (Munro) Ma), Valerianaceae plant Valeriana amurensis Smir. ex Kom (Valeriana amurensis P.Smirn.) over-ground part and caprifoliaceae plant honeysuckle (Lonicera japonica Thunb.) etc.Luteolin has following pharmacological action: 1) anti-inflammatory activity of anti-inflammatory luteolin and the generation that suppresses nitrogen protoxide and other inflammatory cytokines, and the phosphorylation of inhibition tyrosine is relevant with the genetic expression of nuclear factor mediation.2) antibacterial luteolin can suppress the bacterium such as staphylococcus, staphylococcus aureus, intestinal bacteria, herpes simplex, Bacillus subtilus, card ground, white beads, typhoid fever, dysentery and poliomyelitis, cells of coxsackie B 3 virus, hiv virus HIV-1, H.suis virus; 3) but strengthen immunity enhancing antibody growing amount, the splenic T lymphproliferation response is all had promoter action, bone-marrow-derived lymphocyte is had immuno-potentiation; 4) the spasmolysis luteolin can obviously suppress the contraction of unstriated muscle supersensitivity, also can suppress vas deferens and shrink; 5) antitumor luteolin all has restraining effect to ascites cells body, prostate gland and breast cancer cell, can significantly reduce the incidence of colorectal carcinoma, suppresses the invasion and attack motor capacity of ovarian cancer cell; 6) but the transformation reactions mediator that antianaphylaxis luteolin Immunosuppression sphaeroprotein produces, its effect may with suppress Ca
2+Interior stream is relevant with protein kinase transposition activation; 7) anti-inflammatory demyelination luteolin can be protected spongiocyte, suppresses scavenger cell to the phagolysis of myelin; 8) the anti-fibrosis luteolin can suppress the propagation of hepatic stellate cell and collagen is synthetic, reduces degree of hepatic fibrosis, and can improve the pulmonary fibrosis lesion tissue, suppresses the propagation of human lung fibroblast, promotes its apoptosis; 9) antifertility and hormonal action luteolin can increase weight, diameter, the endometrial thickness in uterus after oral, have estrogen-like effects; 10) can increase coronary artery blood flow to the effect of blood vessel, strengthen the effect of capillary vessel, reduce blood cholesterol, suppress tumor growth and vascularization, have the auterial diastole effect.Luteolin can be used for following Chinese patent medicine: Radix Lamiophlomidis Rotatae capsule; MAISHU Capsules; Late autumn frondosa oral liquid.
At present the preparation Reseda odorata have four kinds of methods: 1) plant extract: extract from the plant Folium chrysanthemi that contains luteolin or Pericarppium arachidis hypogaeae.Medicinal material adds the organic solvent refluxing extraction, extracts degreasing after the extracting solution concentrating under reduced pressure, and degreasing water liquid is with absorption with macroporous adsorbent resin, be washed with water to effluent liquid colourless after, with ethanol elution, concentrating under reduced pressure, recrystallization, vacuum-drying, obtain the luteolin sterling, output is not high, and technique is loaded down with trivial details.2) complete synthesis: Phloroglucinol and 3,4-dimethoxy benzoyl acetic acid ethyl ester is 140~160 ℃ of high temperature, vacuum (1330Pa) is lower to reflux 2 hours, add phenyl ether to continue again to react dealcoholysis in 4~5 hours dehydration after slightly cold, cooling rear suction filtration, add 95% ethanol obtain intermediate 3 ', 4 '-dimethoxy-CR.3 ', 4 '-dimethoxy-5, the 7-dihydroxyflavone adds the catalyzer anhydrous pyridine, add again the catalyzer aluminum chloride under 100 ℃, 160~180 ℃ of reactions sloughed 3 in 3~5 hours ', two methyl on 4 ' number position, reactant is put into water and is hydrolyzed, the cooling luteolin crude product that obtains obtains the luteolin sterling after crude product washing, recrystallization.This method yield is low.3) biosynthesizing: LeonardE etc. have set up the approach of 4 a steps restructuring flavanone that is made of styracin-4-hydroxylase, CoA ligase, chalcone synthetase, chalcone isomerase etc.The flavones synthetic enzyme is introduced in the flavanone restructuring yeast strains, can be the flavones molecule with multiple phenol propyl alcohol acids precursor conversion, this method more complicated, also not industrialization so far.4) semi-synthetic: dehydrogenation reaction, Hesperidin dehydrogenation under iodine/pyridine, iodine/dimethyl sulfoxide (DMSO)/systems such as sulfuric acid, 50~120 ℃ of temperature of reaction, 5~16 hours reaction times, alkali lye dissolving after the precipitate washing, add again methyl alcohol and regulate pH to acid, obtain diosmin after precipitate suction filtration, washing, drying.The reaction of hydrolysis desugar glycosides, diosmin be at methyl alcohol/hydrochloric acid, ethylene glycol/sulfuric acid, ethylene glycol/hydrochloric acid, ethanol/hydrochloric acid, hydrolysis desugar glycosides under the hydrolyzation systems such as methyl alcohol/sulfuric acid, 50~120 ℃ of temperature of reaction, in 1~5 hour reaction times, cooling precipitate obtains diosmetin through the organic solvent recrystallization.Demethylating reaction, diosmetin is demethylation under the demethylation reagent systems such as Hydrogen bromide, Hydrogen bromide/diacetyl oxide, hydroiodic acid HI/diacetyl oxide, 70~120 ℃ of temperature of reaction, 5~12 hours reaction times, after cooling yellow product suction filtration of separating out, washing is to neutral, cryodrying obtains the luteolin crude product, obtains light yellow luteolin sterling after the organic solvent recrystallization.Take Hesperidin as raw material, through hydrolysis, dehydrogenation, the demethylation three-step reaction obtains luteolin.This method raw material is easy to get, and yield is high, the most easily realizes industrialization.
The present invention is take Hesperidin as raw material, through hydrolysis, and demethylation, the dehydrogenation three-step reaction obtains luteolin.Passing by the first dehydrogenation of Hesperidin is hydrolyzed again, and this method significantly reduces with the iodine amount, and production cost is very low, and a kind of technology of preparing of eriodictyol also is provided simultaneously.
Summary of the invention
The preparation of the first Hesperitin: Hesperidin adds activated carbon decolorizing with the acid ethanol solution heating hydrolysis, filtered while hot, and filtrate is concentrated, the concentrated solution aqueous precipitation, press filtration, washing, drying obtains Hesperitin.
The preparation of the second eriodictyol: Hesperitin adds the anhydrous chlorides of rase reactive aluminum after dissolving with the sulfur oxychloride reflux, adds activated carbon decolorizing, filtered while hot, and filtrate is concentrated, the concentrated solution aqueous precipitation, press filtration, washing, drying obtains eriodictyol.
The preparation of the 3rd luteolin crude product: eriodictyol adds the iodine dehydrogenation reaction with the pyridine heating for dissolving, obtains the luteolin reaction solution.The reaction solution concentrating under reduced pressure, the concentrated solution aqueous precipitation, press filtration, washing, filtration cakes torrefaction obtains the luteolin crude product.
The preparation of the 4th luteolin elaboration: the crude product luteolin dissolves with alcohol heating reflux, adds activated carbon decolorizing, filtered while hot, and filtrate is concentrated, crystallization, centrifugal, drying obtains the elaboration diosmetin.
Description of drawings
Fig. 1 is synthetic route chart
Embodiment
The preparation of the first Hesperitin: sealed the reactor mouth, in 1000Kg ethanol suction reactor with accurate measurement, ethanol is transferred pH1~2 with the vitriol oil, slowly add Hesperidin crude product 80Kg from the reactor mouth, the sealed reactor mouth starts stirring, opens the heating of reactor heat-carrying steam valve, open circulating condensing water, 70~75 ℃ of back flow reaction.Detect from the thief hole sampling after reaction 10h, after reacting completely, then add 2kg gac rear enclosed still mouth, open reactor heat-carrying steam valve, question response still temperature rises to 75 ℃, and off-response still heat-carrying steam when pressure rises to 0.11MPa~0.13MPa keeps this condition to stir decolouring 30min.Begin to concentrate, until the concentrated solution alcoholic strength reaches 15~25%, add the purified water of 10 times of amounts, fully stir, precipitation, press filtration, 60~70 ℃ of dry 8h obtain Hesperitin 45.6Kg.
The preparation of the second eriodictyol: take the 300.0kg sulfur oxychloride, with vacuum suction reactor, start stirring, slowly add successively Hesperitin 100.0kg from charging opening in batches, Aluminum chloride anhydrous 3kg, the sealing charging opening slowly is heated to 80~110 ℃, and keeps this thermotonus 15~20h under stirring.Every temperature of two hour records, after timing is completed, open cooling water temperature to 20~30 ℃, sample thief detects the content of eriodictyol, qualified after, then add 2kg gac rear enclosed still mouth, open reactor heat-carrying steam valve, question response still temperature rises to 75 ℃, insulated and stirred 30min, the feed liquid suction vacuum concentration pot that decolouring is good, concentrated, add 15 times of amounts of purified water, fully stir, precipitation is used 60m
2The plate-and-frame filter press press filtration, filtrate with purified water be washed till effluent liquid be close to colourless after, discharging, the oven dry, obtain eriodictyol.
The preparation of the 3rd luteolin: in the retort of 0.5Ton with vacuum suction 300kg pyridine, add the 100kg eriodictyol from the tank mouth, add iodine 2kg, the sealed reactor mouth starts stirring, opens the heating of reactor heat-carrying steam valve, open circulating condensing water, at 90~100 ℃ of reaction 18h, detect from the thief hole sampling, after reacting completely, begin to concentrate, until concentrated solution proportion reaches 1.05~1.10, add the purified water of 10 times of amounts, fully stir, precipitation 24h, with the plate-and-frame filter press press filtration, at 60~80 ℃ of dry 10h, obtain the luteolin crude product.Crude product 50kg is dissolved with the 400kg alcohol heating reflux, add the 1.5kg gac, at 70~76 ℃ of lower insulated and stirred 30min, filtered while hot, filtrate decompression are concentrated into alcoholic strength 15~20%, and concentrated solution is placed 20h under 15~20 ℃, centrifugal, at 60~80 ℃ of dry 4h, obtain luteolin elaboration 42kg, content 98.6%.
Claims (6)
1. the novel process of a semi-synthetic preparation luteolin, is characterized in that, take Hesperidin as raw material, the method is successively through following steps:
(1) Hesperidin is hydrolyzed with acid ethanol solution, after hydrolysis fully, adds activated carbon decolorizing, filtered while hot, and filtrate is concentrated, the concentrated solution aqueous precipitation, press filtration, washing, drying obtains Hesperitin.
(2) Hesperitin dissolves with sulfur oxychloride, adds the Aluminum chloride anhydrous demethylation, obtains the eriodictyol reaction solution, adds activated carbon decolorizing, filtered while hot, and filtrate is concentrated, the concentrated solution aqueous precipitation, press filtration, washing, filtration cakes torrefaction obtains eriodictyol.
(3) eriodictyol with the pyridine heating for dissolving after, add iodine oxydehydrogenation, obtain the luteolin reaction solution.Concentrating under reduced pressure is removed impurity, press filtration, and drying obtains the crude product luteolin.
(4) the crude product luteolin dissolves with alcohol heating reflux, adds activated carbon decolorizing, filtered while hot, and filtrate is concentrated, crystallization, centrifugal, drying obtains the elaboration luteolin.
2. the novel process of a kind of semi-synthetic preparation luteolin described according to right 1, it is characterized in that, in step (1), the ethanol consumption is 10~15 times (W/W) of Hesperidin amount, ethanol is take the dilute sulphuric acid adjust pH as 1~2, hydrolysis temperature is 70~75 ℃, time 12~24h, activated carbon dosage is 3~5% of raw material Hesperidin amount, concentrating under reduced pressure, concentrated solution alcoholic strength are lowered the temperature to alcoholic degree 15~25%, the purified water that adds 10 times of (V/V) amounts of concentrated solution, precipitation, press filtration is washed to filtrate and is neutral.60~70 ℃ of drying 4~8h.
3. the novel process of a kind of semi-synthetic preparation luteolin described according to right 1, it is characterized in that, in step (2), the sulfur oxychloride consumption is 3~6 times (V/W) of Hesperitin, the Aluminum chloride anhydrous consumption is 0.05~0.1 times (W/W) of Hesperitin, reaction times is 15~20h, 80~110 ℃ of temperature of reaction.Activated carbon dosage is 3~5% of Hesperitin amount, and concentrating under reduced pressure adds the purified water of concentrated solution 15 times (V/V) amount, precipitation, press filtration, 60~70 ℃ of dry 10h.
4. the novel process of a kind of semi-synthetic preparation luteolin described according to right 1, is characterized in that, in step (3), the pyridine consumption is 3~6 times (V/W) of eriodictyol amount, and the consumption of iodine is 1~3% of eriodictyol amount, reaction times 18~22h; 90~100 ℃ of temperature of reaction.Reaction solution is concentrated into proportion 1.05~1.10, adds 5 times of amount purified water, fully stirs, and removes impurity, press filtration, filter cake oven dry.
5. the novel process of a kind of semi-synthetic preparation luteolin described according to right 1, it is characterized in that, in step (4), the ethanol consumption is 7~10 times (W/W) of crude product luteolin, activated carbon dosage is 3~5% of crude product luteolin amount, concentrating under reduced pressure, the concentrated solution alcoholic strength is 15~20%, 15~20 ℃ of Tcs.
6. according to right 1,2, the novel process of 3,4,5 described a kind of semi-synthetic preparation luteolins, it is characterized in that, the technology for preparing luteolin take Hesperidin as raw material also comprises a kind of technology of preparing of eriodictyol in fact, and namely Hesperidin first is hydrolyzed to Hesperitin, Hesperitin demethylation again obtains eriodictyol, and in dehydrogenation, the consumption of iodine significantly reduces.In whole reaction process, the yield of luteolin can reach 40.2%, and content reaches 98.6%.
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103833714A (en) * | 2014-02-23 | 2014-06-04 | 闻永举 | Semi-synthesis method of luteolin and galuteolin as well as luteolin rutinoside |
CN104327136A (en) * | 2014-11-19 | 2015-02-04 | 陕西嘉禾植物化工有限责任公司 | Preparation method of eriocitrin |
CN104610400A (en) * | 2015-01-14 | 2015-05-13 | 绵阳迪澳药业有限公司 | Method for synthesizing eriocitrin from hesperidin |
CN108315343A (en) * | 2018-02-11 | 2018-07-24 | 楚雄医药高等专科学校 | A kind of method for synthesizing gene of production cyanidenon yeast strain and bacterial strain and application |
CN109180628A (en) * | 2018-10-24 | 2019-01-11 | 陕西嘉禾生物科技股份有限公司 | A kind of preparation method of apiolin |
CN112851616A (en) * | 2021-01-25 | 2021-05-28 | 三原润禾生物科技有限公司 | Semi-synthesis method of eriodictyol |
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JPH09143070A (en) * | 1995-09-22 | 1997-06-03 | Nippon Flour Mills Co Ltd | Inhibitory agent for lipase and lowering agent for triglyceride in blood |
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103833714A (en) * | 2014-02-23 | 2014-06-04 | 闻永举 | Semi-synthesis method of luteolin and galuteolin as well as luteolin rutinoside |
WO2015124113A1 (en) * | 2014-02-23 | 2015-08-27 | 闻永举 | Semi-synthesis method for luteolin, galuteolin and luteolin rutinoside |
CN103833714B (en) * | 2014-02-23 | 2016-07-13 | 闻永举 | Luteolin, luteoloside, the semisynthetic method of luteolin rutinoside |
CN104327136A (en) * | 2014-11-19 | 2015-02-04 | 陕西嘉禾植物化工有限责任公司 | Preparation method of eriocitrin |
CN104610400A (en) * | 2015-01-14 | 2015-05-13 | 绵阳迪澳药业有限公司 | Method for synthesizing eriocitrin from hesperidin |
CN108315343A (en) * | 2018-02-11 | 2018-07-24 | 楚雄医药高等专科学校 | A kind of method for synthesizing gene of production cyanidenon yeast strain and bacterial strain and application |
CN109180628A (en) * | 2018-10-24 | 2019-01-11 | 陕西嘉禾生物科技股份有限公司 | A kind of preparation method of apiolin |
CN112851616A (en) * | 2021-01-25 | 2021-05-28 | 三原润禾生物科技有限公司 | Semi-synthesis method of eriodictyol |
CN112851616B (en) * | 2021-01-25 | 2023-09-26 | 三原润禾生物科技有限公司 | Semisynthesis method of eriodictyol |
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Application publication date: 20130612 |