CN103772336A - Semi-synthesis method of phenolic hydroxyl flavonoid compounds and iodine recycling method - Google Patents

Semi-synthesis method of phenolic hydroxyl flavonoid compounds and iodine recycling method Download PDF

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CN103772336A
CN103772336A CN201410059636.3A CN201410059636A CN103772336A CN 103772336 A CN103772336 A CN 103772336A CN 201410059636 A CN201410059636 A CN 201410059636A CN 103772336 A CN103772336 A CN 103772336A
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CN103772336B (en
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闻永举
申秀丽
粱爱军
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Qianxi Chestnut Industry Research Development Center
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    • 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
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    • C01B7/00—Halogens; Halogen acids
    • C01B7/13—Iodine; Hydrogen iodide
    • C01B7/14—Iodine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
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    • C07H17/07—Benzo[b]pyran-4-ones

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Abstract

The invention discloses a semi-synthesis method of phenolic hydroxyl flavonoid compounds and an iodine recycling method, relating to two ways A and B and iodine recycling, wherein in the way A, flavone is easily dissolved in a pyridine solvent of ethylene glycol or glycerin, and with iodine as a dehydrogenating agent, flavone is generated by heating and dehydration; in the way B, flavanone or flavone is not dissolved in pyridine of alcohol, the complexing of trivalent aluminum and flavanone is adopted, the solubility of the complexing and dehydrogenation products is high in alcohol, flavone is separated from the aluminum complex by use of phosphoric acid and the like, and flavone insoluble in water is separated out and obtained by filtering. The method disclosed by the invention is a universal method for preparing flavonoid compounds through dehydrogenation of phenolic hydroxyl dihydro flavonoids, the dosage of the reagents such as pyridine and the like is very small, and the treatment is simple, so that the method is suitable for industrial production. Take the diosmin preparation using hesperidin as an example, compared with the existing documents and patents, in the method disclosed by the invention, the dosage of organic solvents such as pyridine and the like is the least, the treatment is the simplest, the yield is the highest, and the method is environment-friendly (iodides can be oxidized by hydrogen peroxide, the recycling process is simple, and the yield is relatively high), and industrial production is easy to realize.

Description

Phenolic hydroxyl group flavonoid compound semisynthesis and iodine recovery method
Technical field
The present invention relates to the dehydrogenation of phenolic hydroxyl group flavanone and generate phenolic hydroxyl group flavonoid compound semisynthesis and iodine recovery method, its field belongs to chemistry, medical.
Background technology
The flavanone kind composition that contains phenolic hydroxyl group: due to natural flavanone kind composition, it is the secondary metabolite of plant, in molecule, conventionally squeeze into the mark of enzyme, contain compared with polyphenol hydroxyl, extensively there is occurring in nature, its rich content, extraction process is simple, cheap as approximately 150 yuan of 90% Hesperidin market value per kilograms, 98% approximately 260 yuan of naringin market value per kilograms.But it is obvious that flavanone kind composition pharmacological action is not so good as flavonoid compound, its reason is that flavonoid compound conjugated structure is better than flavanone kind composition, the former at anti-inflammatory, anti-oxidant, anti-radical action is good compared with the latter, need to prepare diosmin as Hesperidin, naringin or naringenin need to be prepared apigenin etc.
Bromine oxidation dehydrogenation and shortcoming: flavanone kind composition Oxidative Dehydrogenation is for flavonoid compound, and its preparation method has bromine oxidation and iodine oxidation style.In bromine oxidation, in flavanone molecule, without exposed phenolic hydroxyl group, can directly use bromine dehydrogenation, it is with low cost.If but have phenolic hydroxyl group, and for avoiding bromo-reaction, its phenolic hydroxyl group should first be protected, and as methyl-etherified, acetylize, has in the method protection, dehydrogenation, goes protection, causes step many, and yield is on the low side, causes cost high.
The dehydrogenation of iodine oxidation style and shortcoming: in iodine oxidation style, be divided into NaI-DMSO(dimethyl sulfoxide (DMSO)) or I 2-DMSO high-temperature oxidation and I 2-pyridine equal solvent method.The former is applicable in flavanone molecule without exposed phenolic hydroxyl group, with 5, the dehydrogenation of 7,4'-trimethoxy naringenin generates 5,7,4'-trimethoxy apigenin is example explanation, in this method, DMSO doubles as solvent and oxygenant, and DMSO approaches at the temperature of boiling point, can iodine oxide ion to iodine molecule, and iodine can with dihydro Huang
Figure 164395DEST_PATH_IMAGE001
Ketone reacts, and makes its dehydrogenation, generates flavones.Although iodine is expensive, iodine consumption is little, and its cost is also very cheap.The flavanone that contains phenolic hydroxyl group, because DMSO at high temperature also has certain oxidation to phenolic hydroxyl group, destroys flavones parent nucleus, can not use NaI-DMSO(dimethyl sulfoxide (DMSO)) or I 2-DMSO high-temperature oxidation, can only make I 2-pyridine equal solvent method, on the one hand, because of pyridine equal solvent can not iodine oxide ion to iodine molecule, therefore the large usage quantity of iodine causes cost high.The coplanarity of flavonoid compound is better than flavanone kind composition on the other hand, causes flavonoid compound molecule and molecule to be easier to overlapping arrangement, forms crystallization, causes its solubleness in water and organic solvent to diminish, and is easy to separate out.Therefore, the higher or thorough dehydrogenation of flavanone kind composition dehydrogenation product, needs more organic solvent.At conventional organic solvent, as pyridine, DMSO, DMF, wherein the boiling point of DMSO is 189 ℃, and the boiling point of DMF is 152 ℃, and the two boiling point is higher, is difficult to reclaim, and usually used as disposable use, causes high expensive.Moreover, flavonoid compound, as limited in apigenin, diosmetin solubleness in DMSO, DMF, make it dissolve, just need more DMSO, DMF.Pyridine boiling point is 115 ℃, compare first two and can reclaim, but also have problems: first pyridine has alkalescence, the phenolic hydroxyl group salify easily and in flavones molecule, simultaneously also with the hydrogen iodide salify of dehydrogenation generation, the pyridine after salify, boiling point significantly increases.In addition, due to pyridine endless belt π
Figure 612693DEST_PATH_IMAGE002
ring stream of electrons, and flavones because phenolic hydroxyl group on oxygen, there is the pi-conjugated effect of P-, cause the phenyl ring band π in flavones
Figure 392431DEST_PATH_IMAGE003
ring stream of electrons, produce π
Figure 318798DEST_PATH_IMAGE002
---π
Figure 664329DEST_PATH_IMAGE003
complexing, making pyridine be subject to reactive force increases, and further strengthens the difficulty that pyridine reclaims, and the pyridine rate of recovery is not high.Take Hesperidin Oxidative Dehydrogenation for diosmin as example, two kinds of forms of pyridinium salt and pyridine π
Figure 17950DEST_PATH_IMAGE002
---flavones π
Figure 284983DEST_PATH_IMAGE003
complexing action, its reaction formula is as follows.Another through reclaim under reduced pressure, the yield of pyridine only can reach 70%, and the pyridine not reclaiming has obvious pollution to environment.Secondly the cacodorous smell of pyridine, in the process reclaiming, has certain infringement to employee's health.
Figure 15042DEST_PATH_IMAGE005
Figure 215079DEST_PATH_IMAGE007
Phenolic hydroxyl group flavanone kind composition dehydrogenation example: for the flavanone kind composition that contains phenolic hydroxyl group, of a great variety because of it, as Hesperidin, naringin, Hesperitin, naringenin etc., the dehydrogenation of each compound, all can enumerate several methods, particularize difficulty is larger, prepares diosmin as the present situation of the iodo-pyridine of representational explanation to the flavanone that contains phenolic hydroxyl group take Hesperidin.Oranges and tangerines crop is the large trade agricultural-food in third place in the world that the whole world is only second to wheat, corn, is also the large fruit of the first in the world.Before 1978, mandarine annual production is stabilized in 300,000 tons of left and right, and after this output increases year after year, and within 2009, mandarine output exceedes and occupies world-class Brazil continuous decades with 2,500 ten thousand ton.Abundanter containing Hesperidin in oranges and tangerines, must not be lower than 5.0% containing Hesperidin as regulation rascal of 2010 editions Chinese Pharmacopoeias, dried orange peel must not be lower than 3.5% containing Hesperidin.Most of peel of Citrus reticulata Blanco is wasted, only on a small quantity as dried orange peel and extraction Hesperidin.Diosmin is Hesperidin dehydrogenation product, there is the effect of vitamin P sample, can reduce vascular fragility and abnormal permeability, again for preventing and treating hypertension and arteriosclerotic assisting therapy, being used for the treatment of capillary fragility effect is eager to excel, and has the advantages that toxicity is low compared with rutin, Hesperidin.Be used for the treatment of hemorrhoid, chronic venous insufficiency etc., approximately 4000 tons, the Year's consumption whole world, and also consumption is also increasing year by year.Because diosmin is lower in natural content, its preparation method is that Hesperidin dehydrogenation under the effect of iodine generates at present.Because diosmin is water insoluble and majority of organic solvent, therefore prepare in the technique of diosmin at Hesperidin, take pyridine as example, its consumption conventionally reach Hesperidin 5 times of amounts ([1] Gao Yongjin. strengthen intravenous tension medicine diosmin synthesis progress research [J]. China Chemical Industry trade, 2013, (7): 226; [2] Chen Zhiyu. diosmin synthesis technique analyze [J]. Chinese science and technology in length and breadth, 2011, (7): 315; [3] Li Yushan, Wang Jingan. the synthesis technique [J] of diosmin. laboratory study and exploration, 2010,29(8): 39-41; [4] Zhang Guangyue, opens strong. the production method [P] of diosmin. and China, CN101089009A, 2007.12.19).Yang edemas etc. adopt Microwave-assisted firing method, with I 2make catalyzer with NaI, with K 2cO 3, NaOH ethanolic soln and pyridine mixed solvent set up reaction system as action solvent, de-Hesperidin hydroformylation step is prepared to diosmin.Though certain embodiments has avoided high temperature and reaction solvent system to use in a large number the high boiling point such as pyridine, dimethyl sulfoxide (DMSO) noxious solvent, but it is loaded down with trivial details to use the organic solvents such as more methyl alcohol, ethanol and aftertreatment, the synthetic total recovery of diosmin is below 90%, industrialization cost is higher ([5] yang edema still, Liu Maodong, Lei Guoping, Zhu Zhenyu. a kind of diosmin bulk drug synthetic method [P] that meets EP7 version quality standard. China, CN102653549A, 2012.09.05).The production system of a kind of diosmin such as Jin Haixia, is characterized in that, comprise reaction recovery system, in and in filtering system, dissolving crude product filtering system, work in-process and filtering system, be pulverized and mixed system, iodine recovery system, methanol/ethanol recovery system.In reaction process, use a large amount of organic solvents, and the organic solvent rate of recovery only can reach 90%, environmental pollution is larger, and step is more, and its industrialization cost is still higher.([6] Jin Haixia, Yang Xiangnong, Zhao Jingsong, Wang Ping. a kind of production system [P] of diosmin. China, CN202011848U, 2011.10.19).
By Hesperidin-I 2the example of-pyridine dehydrogenation is known, iodo-pyridine to phenolic hydroxyl group flavones certain embodiments in, although condition is comparatively gentle, exist pyridine consumption large, be difficult to reclaim, aftertreatment complexity, yield is on the low side, causes product cost higher, if Hesperidin Oxidative Dehydrogenation is for diosmin.
Summary of the invention
By Given this, according to the flavonoid compound and the pyridine and its derivatives salify that contain phenolic hydroxyl group, at the different solubility of alcohol, design A, two kinds of approach of B: A approach is that flavonoid compound solubleness in pyridines solvent is little, and solubleness is large in pyridines and alcohols mixed solvent; B approach be flavonoid compound in pyridines, or in pyridines and alcohols mixed solvent, solubleness is little.A, two kinds of approach of B, solve preferably the dehydrogenation that contains phenolic hydroxyl group flavanone kind composition and exist pyridine consumption large, and aftertreatment is loaded down with trivial details, the problem that product yield is lower.Preparing diosmin as Hesperidin is example, the method that the present invention is used, and compared with existing any document and patent, method pyridine consumption of the present invention is minimum, and aftertreatment is the simplest, and yield is the highest, and environmental protection is easy to suitability for industrialized production; Consumption of organic solvent is few, and iodine solubleness in acid liquid is little, is easy to reclaim, and the rate of recovery is high, is easy to suitability for industrialized production.Therefore product preparation cost is cheap.
(be mainly applicable to aglycon in A approach, as naringenin, Hesperitin etc.): pyridines solvent, phenolic hydroxyl group flavanone kind composition, alcoholic solvent, iodine mixes, stir, 20 ℃-180 ℃ reacting by heating for some time, form uniform solution, TLC/HPLC/UV follow-up investigations, add a small amount of insurance phenol or reaction product added fast in the buck that contains vat powder, after stirring and dissolving, add rapidly aqueous acid, and stir, airtight placement, separate out flavones precipitation, (acid liquid directly adds hydrogen peroxide in filtration, separate out iodine precipitation), water washing filter cake is to no acidic, drain, then dry or dry, obtain flavonoid compound,
(be mainly applicable to glycosides in B approach, as Hesperidin etc.): add trivalent aluminium ion compound, add rapidly pyridines solvent, mix rapidly (preventing the trivalent aluminium ion compound moisture absorption), add phenolic hydroxyl group flavanone kind composition, alcoholic solvent, iodine mixes, stir, 20 ℃-180 ℃ reacting by heating for some time, form uniform solution, TLC/HPLC/UV follow-up investigations, reaction product is added to the water fast, stirring and dissolving rapidly, add rapidly the dealumination agent aqueous solution, rapid stirring is even, airtight placement, separate out flavones precipitation, (acid liquid directly adds hydrogen peroxide in filtration, separate out iodine precipitation), water washing filter cake, drain, infiltrate filter cake (washing flavones adsorbs a small amount of iodine) with a small amount of 50% ethanol, and washing, drain, then dry or dry, obtain flavonoid compound,
Iodine reclaims: filter acid liquid and directly add hydrogen peroxide, airtight placement, separate out iodine precipitation, acid liquid airtight (preventing iodine volatilization) heating and thermal insulation (the tiny precipitation particles of iodine is assembled fast), forms iodine more irregularly shaped, siphon supernatant liquor (yellowish brown) while hot, residue acid liquid filters, and a small amount of water washing iodine filter cake, by methyl alcohol or dissolve with ethanol for the solid of iodine, steam methyl alcohol or ethanol, then closed sublimation obtains iodine.
The present invention is said containing trivalent aluminium ion compound, mainly refer to aluminum chloride, alchlor, aluminium triiodide, Tai-Ace S 150, aluminum nitrate and aluminium alcoholates (aluminum methylate, ethylene glycol aluminium, glycerol aluminium etc.) etc., itself and flavanone kind composition molar ratio 3:1-1:3, wherein preferred aluminum trichloride (anhydrous), its mole dosage preferably equates with the molar weight of flavanone, with the preferential mixed dissolution of pyridines solvent.
The said phenolic hydroxyl group flavanone kind composition of the present invention, mainly refer to Hesperidin (CAS:520-26-3), Hesperitin-7-O-glucoside (CAS:31712-49-9), Hesperitin (CAS:520-33-2), naringin (CAS:10236-47-2), naringenin (CAS:480-41-1), eriodictyol-7-O-glucoside, eriodictyol (CAS:552-58-9) etc.
The said alcoholic solvent of the present invention, main nail alcohol, dehydrated alcohol, propyl alcohol, Virahol, ethylene glycol, 1,2-PD, 1,3-PD, glycerol, wherein preferred ethylene glycol and glycerol, consumption is not limit; Particular methanol, its volumetric usage is no more than pyridines solvent volume (as pyridine 10ml, methyl alcohol volume is preferably no more than 10ml).
 
The said pyridines solvent of the present invention, mainly refers to pyridine, 2-picoline, 3-picoline, 4-picoline, 5-picoline, 2,6-lutidine etc.
The said dealumination agent of the present invention, mainly refer to various acid and its esters, can be phosphoric acid, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, vat powder, sulfuric acid, hydrochloric acid, Hydrogen bromide, acetic acid, oxalic acid, Citric Acid, tartrate etc., or any two kinds of extremely above mixing are used, wherein preferably phosphoric acid, its consumption and trivalent aluminium mol ratio are not less than 1:1.
The said acid of the present invention, mainly refers to various acid, comprises phosphoric acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, acetic acid, oxalic acid, Citric Acid, tartrate etc., or any two kinds of extremely above use, wherein preferably phosphoric acid, hydrochloric acid, sulfuric acid of mixing.
The said flavones of the present invention, mainly refer to the flavones that contains phenolic hydroxyl group, its representative compound: diosmin (CAS:520-27-4), Rhoifoloside (CAS:17306-46-6), diosmetin (CAS:520-34-3), diosmetin-7-O-glucoside (CAS:20126-59-4), luteolin (CAS:491-70-3), apigenin (CAS:520-36-5), apigenin β-D-7-O-glucoside (CAS:578-74-5).
In A approach, take dibasic alcohol or trivalent alcohol as dehydrogenation solvent, dehydrogenation effect will be got well: generate Rhoifoloside as example explanation take naringin dehydrogenation, when using methyl alcohol-pyridines solvent, its product is the mixture of dehydrogenation product and iodo product, when methanol usage is fewer, dehydrogenation product is more, and iodo product is fewer; In the time of spent glycol-pyridines solvent or glycerol-pyridines solvent, obtain dehydrogenation product, illustrate that ethylene glycol or glycerol can be used as solvent.If not spent glycol, glycerol etc., only using pyridine as solvent with acid scavenger, can separate out precipitation in a large number, if naringenin Oxidative Dehydrogenation is for apigenin, and product is through acid rinsing repeatedly, in drying course, always has pyridine foul smell;
In B approach, utilize trivalent aluminium salt easily and flavanone kind composition complexing, its complex compound and dehydrogenation product are all soluble in alcohol, through heating, form uniform liquid, there is not the inclusion phenomenon of separating out flavones crystallization, therefore there is pyridine consumption few especially, this complex compound is very easily decomposed by dealumination agents such as phosphoric acid salt and flavonoid compounds such as generating aluminum phosphate.Because flavonoid compound is water insoluble, can separate out, filter, to obtain final product; In B method, utilize polyvalent alcohol can dissolve flavanone kind composition, iodine, pyridine and its derivatives, also can be dissolved in polyvalent alcohol through the flavonoid compound generating with iodine dehydrogenation, add in acid and pyridine, flavonoid compound is water insoluble, separate out, filter, to obtain final product;
Once used aluminum trichloride (anhydrous) and Hesperitin, naringenin complexing dehydrogenation, but due to dehydrogenation product aluminum chloride and diosmetin or aluminum chloride and apigenin complexing, its product is water insoluble, need repeatedly process or recrystallization, could obtain good dealuminzation effect, its processing is loaded down with trivial details, not as A method is processed simple.
In the recovery method of iodine, iodine forms irregular solids and pyridine in acid liquid, ethylene glycol, glycerol, methanol usage is relevant, consumption of organic solvent is more, form iodine solids speed also slower, iodine solids is also fewer, therefore in iodine certain embodiments, the reagent dosages such as pyridine, ethylene glycol, glycerol, methyl alcohol will lack, when reactant can not form uniform solution, can suitably add pyridine, ethylene glycol, glycerol, make reaction thoroughly, consumption of organic solvent is minimum, the iodine rate of recovery is the highest, creates best benefit; Because iodine has volatility or sublimability, whole reaction should be airtight.Iodine is slightly soluble in water, and in heat-processed, the aggregation velocity of iodine is accelerated, and is conducive to mutually assemble and form solid, in the time not heating, forms the solid time longer.
In A approach, form mixed solvent with the monohydroxy-alcohols such as methyl alcohol and pyridines solvent, when the volume of the monohydroxy-alcohols such as methyl alcohol is greater than pyridines solvent volume, there is iodo thing to generate.
Pyridine and its derivatives is for must acid scavenger: take naringin as example, glycerol or ethylene glycol is as solvent, when with CaCO 3as acid scavenger, water-bath more than 40 ℃, reacts, and emits CO 2gas, mainly obtains iodo thing after testing, and dehydrogen substance is not obvious; When using pyridine and its derivatives as acid scavenger, main dehydrogen substance, iodo thing is not obvious, illustrate that pyridines solvent is necessary acid scavenger using dibasic alcohol or trivalent alcohol as solvent.
The invention discloses phenolic hydroxy group flavanone and prepare the method for flavones, especially 4=CO, 5-OH flavanone and trivalent aluminium complexing Oxidative Dehydrogenation in alcohol removes the method for flavones aluminium complex for flavones, phosphoric acid, the fastly recovering of iodine, those skilled in the art can use for reference content herein, difference is contained to phenolic hydroxyl group flavanone and suitably improve processing parameter, realize as the kind of adjustment solvent, consumption, temperature etc. the method for preparing flavones.Special needs to be pointed out is, in the process of the various flavanone kind composition Oxidative Dehydrogenations that contain phenolic hydroxyl group for flavones, ethylene glycol or glycerol are as solvent, solublization is played in trivalent aluminium and flavones complexing, phosphoric acid plays arbitrary effect of the complexing action of abolishing flavones and aluminium, and it is included that they all will be regarded as the present invention.Related personnel obviously can not suitably change or change and combine method as herein described, principle in disengaging content of the present invention, spirit and scope, realizes and apply the technology of the present invention.
Owing to relating to the flavanone compounds that contains phenolic hydroxyl group, kind is more, and number is numerous.Therefore, can not be illustrated each glycosides compound, but in order further to understand the present invention, carry out classification declaration with A, two kinds of approach of B, embodiment is as follows:
A approach, reaction product solubleness in the dibasic alcohol of pyridines or trivalent alcohol solution is large, Al 3+complexing is not necessarily:
Embodiment 1
Get 95% Hesperitin 5g in 250ml iodine flask, add 6ml pyridine, 20ml ethylene glycol and 4.2g iodine, stir evenly, 80 ℃ of confined reactions of water-bath (or prolong upper end adds the drying tube of calcium chloride).Every 1h stirs 1 time, is even shape liquid after 2h, continues confined reaction 6h.The powder 0.5g that takes a policy, stirs, and in impouring 300ml 1.5%NaOH solution, after stirring and dissolving, adds hydrochloric acid to be adjusted to acidity rapidly, and after airtight placement 30min, suction filtration, obtains the another device of acid liquid 1(and deposit) and filter cake.Water washing filter cake is to no acidic, and filter cake dissolves with 50% ethanol buck, is being adjusted to pH3-5 with hydrochloric acid, after placement 3h, filter, and a small amount of 50% washing with alcohol filter cake for filter cake, 60 ℃ of oven dry, obtain diosmetin 4.62g, purity 96.2%.
Figure 729478DEST_PATH_IMAGE012
Embodiment 2
Get 95% Hesperitin 5g in 250ml iodine flask, add 2-picoline 6ml, 20ml glycerol and 4.2g iodine, stir evenly, 85 ℃ of confined reactions of water-bath (or prolong upper end adds the drying tube of calcium chloride), stir 1 time, are even shape liquid after 1h, continue confined reaction 7h, the powder 0.5g that takes a policy, stirs, in impouring 300ml 1.5%NaOH solution, stirring and dissolving, adds rapidly phosphoric acid to be adjusted to acidity rapidly, stir, after airtight 30min, suction filtration, obtains the another device of acid liquid 2(and deposits) and filter cake.Water washing filter cake is to no acidic, and with a small amount of 50% washing with alcohol filter cake, 60 ℃ of oven dry, obtain diosmetin 4.68g, purity 96.5%.
Embodiment 3
Get 98% naringin 10g in 250ml iodine flask, add 2-picoline 5ml, 20ml glycerol and 4.3g iodine, stir evenly, 80 ℃ of confined reactions of water-bath (or prolong upper end adds the drying tube of calcium chloride), stir 1 time every 2h, are even shape liquid after 8h, powder 0.5g takes a policy, stir, in the rapid impouring 500ml aqueous solution, stirring and dissolving, add phosphoric acid to be adjusted to acidity, after airtight 5h, suction filtration, obtains the another device of acid liquid 3(and deposits) and filter cake.Water washing filter cake is to no acidic, and filter cake infiltrates washing leaching cake with a small amount of 50% ethanol, and 60 ℃ of oven dry, obtain Rhoifoloside 8.89g, purity 98.9%.
Figure 784021DEST_PATH_IMAGE013
Embodiment 4
Get 98% naringenin 5.0g in 250ml iodine flask, add pyridine 5ml, 20ml ethylene glycol and 4.7g iodine, stir evenly, 90 ℃ of confined reactions of water-bath (or prolong upper end adds the drying tube of calcium chloride), stir, and are even shape liquid after 1h, react again after 6h, (containing 0.2% vat powder) in impouring 300ml 1.5%NaOH solution, stirs rapidly, adds 20% sulfuric acid to be adjusted to acidity, stir, after 30min, suction filtration, obtains the another device of acid liquid 4(and deposits) and filter cake., water washing filter cake is to no acidic, and filter cake infiltrates washing leaching cake with a small amount of 50% ethanol, and 60 ℃ of oven dry, obtain apigenin 4.46g, purity 98.8%.
A approach, reaction product solubleness in the monohydroxy-alcohol solution such as dibasic alcohol, trivalent alcohol or the methyl alcohol of pyridine is little, needs the further solubilising of trivalent aluminium complexing:
Embodiment 5
Take fast aluminum trichloride (anhydrous) 3.5g, add rapidly 16ml pyridine to mix (a large amount of white cigarettes of emerging, emit large calorimetric), add 92% Hesperidin 16.5g, add methyl alcohol 7ml, stir, add again methyl alcohol 8ml, iodine 6.8g, stir, 80 ℃ of confined reactions of water-bath (or prolong upper end adds the drying tube of calcium chloride), stir 1 time every 2h, after 4h, be even syrupy liq, react again after 4h, add 500ml warm water, be stirred to rapidly dissolving, add rapidly phosphoric acid 20ml, stir rapidly, mix thoroughly, after airtight placement 30min, suction filtration, and with 100ml water washing filter cake, obtaining acid liquid 5(is made up of filtrate+washings, another device is deposited) and filter cake.Wash filter cake with water to no acidic and drain again, with 100ml 50% ethanol rinse filter cake, drain (50% ethanol is recyclable), paper using wraps, and 60 ℃ of oven dry obtain khaki color diosmin 15.8g, purity 93. 7%.
Embodiment 6
Fast fetching aluminum trichloride (anhydrous) 7.0g, add rapidly 2-picoline 35ml, add methyl alcohol 10ml, add 92% Hesperidin 33g, iodine 13.5g, add methyl alcohol 15ml, stir after 2min, 80 ℃ of confined reactions of water-bath (or prolong upper end adds the drying tube of calcium chloride), stir 1 time every 2h, after 4h, be even syrupy liq, react again after 4h, add 1000ml warm water, be stirred to rapidly dissolving, add rapidly phosphatase 24 0ml, stir rapidly, mix thoroughly, after airtight placement 60min, suction filtration is also used 300ml water washing filter cake, obtaining acid liquid 6(is made up of filtrate+washings, another device is deposited) and filter cake.Wash again filter cake with water to no acidic and drain.With 200ml 50% ethanol rinse filter cake, to drain, paper using wraps filter cake, and 60 ℃ of oven dry obtain khaki color diosmin 32.1g, purity 93. 5%.
Embodiment 7
Get aluminum trichloride (anhydrous) 3.5g, add 16ml pyridine, add Hesperidin 92%16.5g, add ethylene glycol 25ml, iodine 6.8g, 80 ℃ of confined reactions of water-bath (or prolong upper end adds the drying tube of calcium chloride), stir 1 time every 2h, after 4h, be even syrupy liq, then react after 4h, add 500ml warm water, be stirred to rapidly dissolving, add rapidly phosphoric acid 20ml, stir rapidly, the 500ml that adds water again, mixes airtight cooling thoroughly, suction filtration, and with 200ml water washing filter cake, obtain acid liquid 7 and filter cake.Water washing filter cake is to no acidic and drain.Use 100ml 50% ethanol rinse filter cake again, drain, paper using wraps filter cake, and 60 ℃ of oven dry obtain khaki color diosmin 15.4g, purity 93. 4%.
Embodiment 8
Get aluminum trichloride (anhydrous) 3.5g, add 16ml pyridine, add Hesperidin 92%16.5g, add glycerol 20ml, add iodine 6.8g, stir, 80 ℃ of formation uniform liquids of water-bath, confined reaction (or prolong upper end adds the drying tube of calcium chloride), stir 1 time every 2h, after 4h, be even syrupy liq, then react after 4h, add 500ml warm water, be stirred to rapidly dissolving, add rapidly phosphoric acid 20ml, stir rapidly, then the 500ml that adds water, mix thoroughly, airtight cooling, suction filtration, obtains acid liquid 8 and filter cake.Water washing filter cake is to no acidic and drain.Use 100ml 50% ethanol rinse filter cake again, drain, paper using wraps filter cake, and 60 ℃ of oven dry obtain khaki color diosmin 15.6g, purity 93. 3%.
Embodiment 9
Get aluminum trichloride (anhydrous) 3.5g, after adding 16ml pyridine to mix, add 98% naringin 16.0g, add methyl alcohol 14ml, iodine 7.0g, 80 ℃ of confined reactions of water-bath (or prolong upper end adds the drying tube of calcium chloride).Stir 1 time every 2h, after 4h, be even syrupy liq, then react after 4h, add 500ml warm water, be stirred to rapidly dissolving, add rapidly phosphoric acid 20ml, stir rapidly, then the 500ml that adds water, mixing thoroughly, after airtight placement 5h, suction filtration, obtains acid liquid 9.Water washing filter cake is to no acidic and drain.Use 100ml 50% ethanol rinse filter cake again, drain, paper using wraps, and 60 ℃ of oven dry obtain faint yellow Rhoifoloside 14.7g, purity 98. 2%.
Figure 792932DEST_PATH_IMAGE016
Embodiment 10
Get acid liquid 5, be placed in 500ml round-bottomed flask, add 30% hydrogen peroxide 20ml, after airtight placing response 30min, after 95 ℃ of sealed thermal insulating 5h of water-bath, take out, siphon supernatant liquor 250ml while hot, add water 100ml to round-bottomed flask again, suction filtration, a small amount of water washing round-bottomed flask (round-bottomed flask still has some a small amount of iodine), water washing liquor is suction filtration in the lump, wash 2-3 time, with the iodine in dissolve with methanol filter and filter paper, in round-bottomed flask, 80 ℃ of airtight being distilled in round-bottomed flask without methyl alcohol in gas bath, after 150 ℃ of distillations in gas bath, obtain iodine 6.2g, this iodine can use by direct circulation.
Embodiment 11
Get acid liquid 6, be placed in 2000ml round-bottomed flask, add 30% hydrogen peroxide 50ml, after airtight placing response 30min, after 95 ℃ of sealed thermal insulating 5h of water-bath, take out, siphon supernatant liquor 250ml while hot, add water 100ml to round-bottomed flask again, suction filtration, a small amount of water washing round-bottomed flask (round-bottomed flask still has some a small amount of iodine), water washing liquor is suction filtration in the lump, wash 2-3 time, with the iodine in dissolve with methanol filter and filter paper, in round-bottomed flask, 90 ℃ of airtight being distilled in round-bottomed flask without ethanol in gas bath, after 150 ℃ of distillations in gas bath, obtain iodine 12.7g, this iodine can use by direct circulation.

Claims (8)

1. phenolic hydroxyl group flavonoid compound semisynthesis and iodine recovery method: its specific features is the recovery of A, two kinds of approach of B and iodine:
A approach (is mainly applicable to aglycon, as naringenin, Hesperitin etc.): pyridines solvent, phenolic hydroxyl group flavanone kind composition, alcoholic solvent, iodine mixes, stir, 20 ℃-180 ℃ reacting by heating for some time, form uniform solution, TLC/HPLC/UV follow-up investigations, add a small amount of insurance phenol or reaction product added fast in the buck that contains vat powder, after stirring and dissolving, add rapidly aqueous acid, and stir, airtight placement, separate out flavones precipitation, (acid liquid directly adds hydrogen peroxide in filtration, separate out iodine precipitation), water washing filter cake is to no acidic, drain, then dry or dry, obtain flavonoid compound,
B approach (is mainly applicable to glycosides, as Hesperidin etc.): add trivalent aluminium ion compound, add rapidly pyridines solvent, mix rapidly (preventing the trivalent aluminium ion compound moisture absorption), add phenolic hydroxyl group flavanone kind composition, alcoholic solvent, iodine mixes, stir, 20 ℃-180 ℃ reacting by heating for some time, form uniform solution, TLC/HPLC/UV follow-up investigations, reaction product is added to the water fast, stirring and dissolving rapidly, add rapidly the dealumination agent aqueous solution, rapid stirring is even, airtight placement, separate out flavones precipitation, (acid liquid directly adds hydrogen peroxide in filtration, separate out iodine precipitation), water washing filter cake, drain, infiltrate filter cake (washing flavones adsorbs a small amount of iodine) with a small amount of 50% ethanol, and washing, drain, then dry or dry, obtain flavonoid compound,
Iodine reclaims: filter acid liquid and directly add hydrogen peroxide, airtight placement, separate out iodine precipitation, acid liquid airtight (preventing iodine volatilization) heating and thermal insulation (the tiny precipitation particles of iodine is assembled fast), forms iodine more irregularly shaped, siphon supernatant liquor (yellowish brown) while hot, residue acid liquid filters, and a small amount of water washing iodine filter cake, by methyl alcohol or dissolve with ethanol for the solid of iodine, steam methyl alcohol or ethanol, then closed sublimation obtains iodine.
2. the method for claim 1, it is characterized in that said trivalent aluminium ion compound, mainly refer to aluminum chloride, alchlor, aluminium triiodide, Tai-Ace S 150, aluminum nitrate and aluminium alcoholates (aluminum methylate, ethylene glycol aluminium, glycerol aluminium etc.) etc., itself and flavanone kind composition molar ratio 3:1-1:3, wherein preferred aluminum trichloride (anhydrous), its mole dosage preferably equates with the molar weight of flavanone, with the preferential mixed dissolution of pyridines solvent.
3. the method for claim 1, is characterized in that alcoholic solvent, main nail alcohol, dehydrated alcohol, propyl alcohol, Virahol, ethylene glycol, 1,2-PD, 1,3-PD, glycerol, and wherein preferred ethylene glycol and glycerol, consumption is not limit; Particular methanol, its volumetric usage is no more than pyridines solvent volume (as pyridine 10ml, methyl alcohol volume is preferably no more than 10ml).
4. the method for claim 1, is characterized in that pyridines solvent, mainly refers to pyridine, 2-picoline, 3-picoline, 4-picoline, 5-picoline, 2,6-lutidine etc.
5. the method for claim 1, its feature is at dealumination agent, mainly refer to various acid and its esters, can be phosphoric acid, SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, vat powder, sulfuric acid, hydrochloric acid, Hydrogen bromide, acetic acid, oxalic acid, Citric Acid, tartrate etc., or any two kinds of extremely above mixing are used, wherein preferably phosphoric acid, its consumption and trivalent aluminium mol ratio are not less than 1:1.
6. the method for claim 1, it is characterized in that acid, mainly refer to various acid, comprise phosphoric acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, acetic acid, oxalic acid, Citric Acid, tartrate etc., or any two kinds of extremely above use, wherein preferably phosphoric acid, hydrochloric acid, sulfuric acid of mixing.
7. the method for claim 1, it is characterized in that phenolic hydroxyl group flavanone kind composition, mainly refer to Hesperidin (CAS:520-26-3), Hesperitin-7-O-glucoside (CAS:31712-49-9), Hesperitin (CAS:520-33-2), naringin (CAS:10236-47-2), naringenin (CAS:480-41-1), eriodictyol-7-O-glucoside, eriodictyol (CAS:552-58-9) etc.
8. the method for claim 1, it is characterized in that flavones, mainly refer to the flavones that contains phenolic hydroxyl group, its representative compound: diosmin (CAS:520-27-4), Rhoifoloside (CAS:17306-46-6), diosmetin (CAS:520-34-3), diosmetin-7-O-glucoside (CAS:20126-59-4), luteolin (CAS:491-70-3), apigenin (CAS:520-36-5), apigenin β-D-7-O-glucoside (CAS:578-74-5).
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WO2015124114A1 (en) * 2014-02-23 2015-08-27 闻永举 Phenolic hydroxyl flavone compound semisynthesis method and iodine recovery method
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CN108752402A (en) * 2018-04-26 2018-11-06 杭州泽邦科技有限公司 A kind of high-purity diosmin preparation method
CN108752402B (en) * 2018-04-26 2020-08-07 杭州泽邦科技有限公司 Preparation method of high-purity diosmin
CN111004199A (en) * 2019-12-26 2020-04-14 陕西嘉禾药业有限公司 Preparation method of apigenin
CN111100104A (en) * 2019-12-26 2020-05-05 陕西嘉禾药业有限公司 Preparation method of diosmetin
CN111100104B (en) * 2019-12-26 2022-04-01 陕西嘉禾药业有限公司 Preparation method of diosmetin
CN113698440A (en) * 2020-05-21 2021-11-26 西华大学 Method for preparing diosmin by adopting continuous-flow microreactor
CN113557234A (en) * 2020-06-19 2021-10-26 邦泰生物工程(深圳)有限公司 Semi-synthesis method of apigenin
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CN112843243A (en) * 2021-01-27 2021-05-28 张才来 Preparation method and application of diosmin derivative sustained-release preparation
CN112979603A (en) * 2021-03-08 2021-06-18 宜宾西华大学研究院 Continuous flow micro-channel synthesis process of flavonoid compound

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