WO2015124114A1 - 酚羟基黄酮类化合物半合成方法及碘回收方法 - Google Patents

酚羟基黄酮类化合物半合成方法及碘回收方法 Download PDF

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WO2015124114A1
WO2015124114A1 PCT/CN2015/073239 CN2015073239W WO2015124114A1 WO 2015124114 A1 WO2015124114 A1 WO 2015124114A1 CN 2015073239 W CN2015073239 W CN 2015073239W WO 2015124114 A1 WO2015124114 A1 WO 2015124114A1
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acid
iodine
water
pyridine
cas
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闻永举
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闻永举
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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
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • 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
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones

Definitions

  • the invention relates to a semi-synthesis method for dehydrogenation of phenolic hydroxyl dihydroflavones to phenolic hydroxyflavonoids and a method for recovering iodine, the fields of which belong to chemistry and medicine.
  • Dihydroflavonoids containing phenolic hydroxyl groups Due to the natural dihydroflavonoids, which are secondary metabolites of plants, the enzymes are usually labeled with enzymes and contain more phenolic hydroxyl groups, which are widely found in nature and are abundant. The extraction process is simple and the price is low. For example, the market price of 90% hesperidin is about 150 yuan per kilogram, and the market price of 98% naringin is about 260 yuan per kilogram. However, the pharmacological action of dihydroflavonoids is not as obvious as that of flavonoids. The reason is that the conjugated structure of flavonoids is stronger than that of dihydroflavonoids. The former is worse than anti-inflammatory, anti-oxidant and anti-free radicals, such as orange. The preparation of dexamethasone, naringin or naringenin requires preparation of apigenin and the like.
  • Dehydrogenation by bromination and its disadvantages Dehydrogenation of dihydroflavonoids to prepare flavonoids, which are prepared by bromination and iodine oxidation.
  • the bromination oxidation method there is no naked phenolic hydroxyl group in the dihydroflavonoid molecule, and the liquid bromine can be directly used for dehydrogenation, and the cost is low.
  • the phenolic hydroxyl group in order to avoid the bromination reaction, the phenolic hydroxyl group should be protected first, such as methyl etherification and acetylation. In the method, there are protection, dehydrogenation and deprotection, resulting in many steps and low yield. Lead to high costs.
  • iodine oxidation Dehydrogenation by iodine oxidation and its disadvantages: In the iodine oxidation method, it is divided into NaI-DMSO (dimethyl sulfoxide) or I 2 - DMSO high temperature oxidation method and I 2 - pyridine solvent method. The former is suitable for the absence of naked phenolic hydroxyl groups in the dihydroflavonoid molecule, and the dehydrogenation of 5,7,4'-trimethoxynaringen to form 5,7,4'-trimethoxy apigenin is illustrated in the method.
  • DMSO acts as both a solvent and an oxidizing agent. When DMSO is near the boiling point, it can oxidize iodide ions to iodine molecules, while iodine can be combined with dihydro yellow.
  • the ketone reacts to dehydrogenate it to form flavonoids.
  • iodine is expensive, the amount of iodine is small and its cost is low.
  • Dihydroflavonoids containing phenolic hydroxyl groups due to the oxidation of phenolic hydroxyl groups by DMSO at high temperatures, destroying the flavonoid nucleus, can not use NaI-DMSO (dimethyl sulfoxide) or I 2 -DMSO high temperature oxidation method, can only make A solvent method such as I 2 -pyridine, on the one hand, a solvent such as pyridine cannot oxidize iodide ions to iodine molecules, so the amount of iodine is large, resulting in high cost.
  • the coplanarity of the flavonoids is better than that of the dihydroflavonoids, so that the molecules and molecules of the flavonoids are more likely to overlap and form crystals, resulting in less solubility in water and organic solvents, and easy precipitation. Therefore, the dehydrogenation product of the dihydroflavonoid has a higher or complete dehydrogenation, and requires more organic solvent.
  • organic solvents such as pyridine, DMSO, DMF, wherein DMSO has a boiling point of 189 ° C and DMF has a boiling point of 152 ° C, both have a high boiling point and are difficult to recover, and are usually used as a single use, resulting in high cost.
  • flavonoids such as apigenin and geranin have limited solubility in DMSO and DMF, and more DMSO and DMF are required to dissolve them.
  • the boiling point of pyridine is 115 ° C, which can be recovered compared with the former two, but there are also many problems: first, pyridine is basic, easy to form a salt with the phenolic hydroxyl group in the flavonoid molecule, and also forms a salt with hydrogen iodide formed by dehydrogenation. The pyridine after salt formation has a markedly increased boiling point.
  • pyridine has a foul smell, and in the process of recycling, it has certain damage to the employee's body.
  • Examples of dehydrogenation of phenolic hydroxy dihydroflavonoids For dihydroflavonoids containing phenolic hydroxyl groups, due to their wide variety, such as hesperidin, naringin, hesperetin, naringenin, etc., each compound Dehydrogenation can be exemplified by several methods, and it is difficult to enumerate one by one.
  • the present invention which is prepared by using hesperidin as a representative, illustrates the current state of iodine-pyridine on the flavonoids containing phenolic hydroxyl groups.
  • the citrus crop is the third largest trade agricultural product in the world after wheat and corn, and the world's largest fruit.
  • Desamine is a dehydrogenation product of hesperidin, which has a vitamin P-like effect, can reduce vascular fragility and abnormal permeability, and is also used as an auxiliary treatment for prevention and treatment of hypertension and arteriosclerosis, and is used for treating capillary fragility.
  • Rutin and hesperidin are strong and have low toxicity. It is used to treat acne, chronic venous insufficiency, etc. The annual consumption is about 4,000 tons, and the dosage is increasing year by year. Since diosmin is lower in natural content, its preparation method is currently dehydrogenation of hesperidin under the action of iodine.
  • Jin Haixia and other production systems of Diosmin including reaction recovery system, neutralization filtration system, crude product dissolution filtration system, semi-finished product and filtration system, pulverization mixing system, iodine recovery system, methanol ethanol recovery system .
  • reaction recovery system neutralization filtration system
  • crude product dissolution filtration system crude product dissolution filtration system
  • semi-finished product and filtration system pulverization mixing system
  • iodine recovery system methanol ethanol recovery system
  • the solubility of the alcohol is different, and the two pathways A and B are designed:
  • the A pathway is a flavonoid compound having a small solubility in a pyridine solvent, and The solubility in the mixed solvent of pyridine and alcohol is large;
  • the B route is a flavonoid compound having a small solubility in a pyridine, or a mixed solvent of a pyridine and an alcohol, and after dehydrogenation, at a temperature above 100 ° C, and prolonging the reaction time,
  • the flavonoid glycosides can be directly de-saccharified to form flavonoid aglycones on the basis of dehydrogenation.
  • naringin can be directly dehydrogenated and then de-sugared to prepare apigenin.
  • the two methods A and B can better solve the problem that the amount of pyridine in the dehydrogenation containing phenolic hydroxyl dihydroflavonoid compound is large, the post-treatment is cumbersome, and the product yield is low.
  • the method used in the present invention has the lowest dosage of pyridine, the simplest post-treatment, the highest yield, green environmental protection, and easy industrial production compared with any existing literature and patents.
  • the organic solvent is used in a small amount, the solubility of iodine in the acid water solution is small, the recovery is easy, the recovery rate is high, and the industrial production is easy. Naringin can directly prepare apigenin by one-step dehydrogenation and de-sugarization. Therefore, the product preparation cost is low.
  • a route (mainly suitable for aglycons, such as naringenin, hesperetin, etc.): pyridine solvent, phenolic hydroxy dihydroflavonoids, alcohol solvent, iodine mixed, stirred, heated at 20 ° C -180 ° C for a period of time Time, form a uniform solution, TLC / HPLC / UV follow-up inspection, add a small amount of insurance phenol or quickly add the reaction product to the alkaline water containing the powder, stir and dissolve, quickly add the acid aqueous solution, and stir evenly, sealed, precipitated flavonoids , filtered (acid water solution through the macroporous adsorption resin to remove a small amount of flavonoids, washed with water, the aqueous acid solution and water washing solution directly added with hydrogen peroxide, overnight, precipitation of iodine precipitation), water washing filter cake to no acid, pumping Dry, then dried or aired to obtain flavonoids;
  • the B pathway (mainly suitable for glycosides, such as hesperidin, etc.): adding a trivalent aluminum ion compound, rapidly adding pyridine Solvent-like, rapid mixing (to prevent the absorption of trivalent aluminum ion compounds), adding phenolic hydroxyl dihydroflavonoids, alcohol solvent, iodine mixture, stirring, heating at 20 ° C -180 ° C for a period of time to form a homogeneous solution, TLC /HPLC/UV tracking check, the reaction product is quickly added to water, rapidly stirred and dissolved, and the dealuminating agent aqueous solution is quickly added, and the pyridine is neutralized with a strong acid such as hydrochloric acid, and the mixture is quickly stirred uniformly, and the mixture is placed in a closed state to precipitate a flavonoid precipitate, which is filtered (the acid water is passed through).
  • the water is washed with water, the aqueous acid solution and the aqueous washing liquid are directly added with hydrogen peroxide, and the iodine precipitate is precipitated overnight, and the filter cake is washed with water, drained, and the filter cake is wetted with a small amount of 50% ethanol ( Washing flavonoids to adsorb a small amount of iodine), washing, drying, and then drying or drying, to obtain flavonoids;
  • Iodine recovery filtered acid water and water washing liquid directly added with hydrogen peroxide, sealed (to prevent iodine volatilization), overnight, precipitated iodine precipitation, siphon supernatant (yellow brown), residual acid water filtered, a small amount of water to wash iodine The filter cake is then sublimed and sublimed to obtain iodine.
  • the trivalent aluminum ion-containing compound referred to in the present invention mainly refers to aluminum trichloride, aluminum tribromide, aluminum triiodide, aluminum sulfate, aluminum nitrate, and aluminum alcohol (methanol aluminum, ethylene glycol aluminum, glycerol).
  • Aluminum or the like, and its molar ratio to dihydroflavonoids is from 3:1 to 1:3, of which anhydrous aluminum trichloride is preferred, and the molar amount thereof is preferably equal to the molar amount of the dihydroflavonoid, and is preferentially mixed with the pyridine solvent. Dissolved.
  • the phenolic hydroxy dihydroflavonoid compound of the present invention mainly refers to hesperidin (CAS: 520-26-3), hesperetin-7-O-glucoside (CAS: 31712-49-9), orange peel (CAS: 520-33-2), naringin (CAS: 10236-47-2), naringenin (CAS: 480-41-1), naringenin-7-O-glucoside, holy grass Phenol (CAS: 552-58-9) and the like.
  • the alcohol solvent referred to in the present invention mainly refers to methanol, absolute ethanol, propanol, isopropanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, glycerin, of which ethylene glycol and ethylene are preferred.
  • Triol the amount is not limited; preferably methanol, the volume of which does not exceed the volume of the pyridine solvent (such as 10ml of pyridine, the volume of methanol is preferably not more than 10ml, and if dehydrogenation after dehydrogenation, the alcohol can not choose multi-methanol, also Can not add alcohol).
  • the pyridine solvent referred to in the present invention mainly means pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 5-methylpyridine, 2,6-lutidine or the like.
  • the dealuminizing agent according to the present invention mainly refers to various acids and salts thereof, and may be phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, insurance powder, sulfuric acid, hydrochloric acid, hydrobromic acid, acetic acid, oxalic acid, hydrazine. Acid, tartaric acid, etc., or any combination of two or more, preferably phosphoric acid, the amount of which is not lower than the molar ratio of trivalent aluminum At 1:1.
  • the acid referred to in the present invention mainly refers to various acids, including phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, acetic acid, oxalic acid, citric acid, tartaric acid, etc., or a mixture of any two or more, preferably phosphoric acid, hydrochloric acid, sulfuric acid.
  • the flavonoids referred to in the present invention mainly refer to flavonoids containing phenolic hydroxyl groups, and representative compounds thereof: diosmin (CAS: 520-27-4), wild lacquer glycosides (CAS: 17306-46-6), geranium lignin (CAS: 520-34-3), geranin-7-O-glucoside (CAS: 20126-59-4), luteolin (CAS: 491-70-3), apigenin (CAS: 520- 36-5), apigenin ⁇ -D-7-O-glucoside (CAS: 578-74-5).
  • diosmin CAS: 520-27-4
  • wild lacquer glycosides CAS: 17306-46-6
  • geranium lignin CAS: 520-34-3
  • geranin-7-O-glucoside CAS: 20126-59-4
  • luteolin CAS: 491-70-3
  • apigenin CAS: 520- 36-5
  • the diol or triol is used as the dehydrogenation solvent, and the dehydrogenation effect is better: taking the naringin dehydrogenation to form the laccase, as an example, when the methanol-pyridine solvent is used, the product is dehydrogenated. a mixture of the product and the iodine product, the smaller the amount of methanol, the more the dehydrogenation product, the less the iodine product; when using the ethylene glycol-pyridine solvent or the glycerol-pyridine solvent, the dehydrogenation product is obtained. It is indicated that ethylene glycol or glycerol can be used as a solvent. If ethylene glycol, glycerol, etc.
  • the trivalent aluminum salt is easily complexed with the dihydroflavonoid compound, and the complex and the dehydrogenated product are easily dissolved in the alcohol, and heated to form a uniform liquid, and there is no inclusion phenomenon of precipitated flavonoid crystals. Therefore, the amount of pyridine is particularly small, and the complex is easily decomposed by a dealuminizing agent such as phosphoric acid to form a salt such as aluminum phosphate and a flavonoid compound.
  • the flavonoids are insoluble in water, they can be precipitated and filtered, that is, in the B method, the dihydroflavonoids, iodine, pyridine and derivatives thereof can be dissolved by methanol or polyol, and the flavonoids formed by dehydrogenation of iodine can be obtained.
  • the compound can also be dissolved in the polyol, and the acid is neutralized with pyridine.
  • the flavonoid compound is insoluble in water, precipitated, filtered, and obtained;
  • the amount of iodine formed in the irregular solids and the acid water solution is related to the amounts of pyridine, ethylene glycol, glycerol and methanol.
  • the reaction is thorough, the amount of organic solvent is the least, and the iodine recovery rate is the highest, which creates the best benefit; since the acid water containing iodide ion still contains a small amount of flavonoids, a small amount of flavonoids in the acid water solution can be removed by a macroporous adsorption resin such as D101.
  • the compound was added with hydrogen peroxide and allowed to stand overnight to precipitate a higher purity of black iodine.
  • a mixed solvent of a monohydric alcohol such as methanol and a pyridine solvent is used.
  • a monohydric alcohol such as methanol
  • a pyridine solvent is used.
  • Pyridine and its derivatives are necessary acid scavengers: naringin, for example, glycerol or ethylene glycol as solvent, when CaCO 3 is used as acid scavenger, water bath is above 40 ° C, reaction occurs, and CO 2 gas is released. After the detection, the iodide is mainly obtained, and the dehydrogenation is not obvious; when pyridine and its derivatives are used as the acid scavenger, the dehydrogenate is mainly obtained, and the iodide is not obvious, indicating that the diol or the triol is used as the solvent, and the pyridine is used. Solvent-like solvents are necessary acid scavengers.
  • the method for rapid recovery of iodine can further deglucose the glycosides and directly form aglycones.
  • Those skilled in the art can learn from the contents of the present invention to appropriately improve the process parameters of different phenolic dihydroflavonoids, such as adjusting the solvent.
  • a method for preparing flavonoids by type, amount, temperature, and the like.
  • the reaction product has a large solubility in a pyridine diol or triol solution, and Al 3+ complexation is not necessary:
  • the filter cake was washed with water until it was not acidic.
  • the filter cake was dissolved in 50% ethanol alkali water, adjusted to pH 3-5 with hydrochloric acid, left for 3 hours, filtered, and the filter cake was washed with a small amount of 50% ethanol and dried at 60 ° C.
  • the geranin was 4.62 g and the purity was 96.2%.
  • the filter cake was washed with water until it was not acidic.
  • the filter cake was washed with a small amount of 50% ethanol and dried at 60 ° C to obtain 4.68 g of geranyl lignin with a purity of 96.5%.
  • naringin 10g in 250ml iodine flask, add 2-methylpyridine 5ml, 20ml glycerol and 4.3g iodine, stir well, and seal in water bath at 80 °C (or dry calcium chloride at the upper end of the condensing tube) Tube), stirring once every 2 hours, after 8h, it is a uniform liquid, adding 0.5g of insurance powder, stirring evenly, quickly pouring into 500ml aqueous solution, stirring and dissolving, adding phosphoric acid to acidity, sealing for 5h, suction filtration, Acid water 3 (storage) and filter cake. The filter cake was washed with water until it was not acidic. The filter cake was washed with a small amount of 50% ethanol to wash the filter cake, and dried at 60 ° C to obtain 8.89 g of wild lacquerin with a purity of 98.9%.
  • naringenin 5.0g in a 250ml iodine measuring flask add 5ml of pyridine, 20ml of ethylene glycol and 4.7g of iodine, stir well, and seal in a water bath at 90 °C (or a drying tube with calcium chloride at the upper end of the condensing tube).
  • the filter cake was washed with water until it was not acidic.
  • the filter cake was washed with a small amount of 50% ethanol to wash the filter cake, and dried at 60 ° C to obtain 4.46 g of apigenin with a purity of 98.8%.
  • the reaction product has a small solubility in a solution of a diol in a monohydric alcohol such as a diol, a triol or a methanol, and requires trivalent aluminum complex to further solubilize:
  • the filter cake was washed with water until it was not acidic and drained.
  • the filter cake was rinsed with 100 ml of 50% ethanol, drained (recoverable with 50% ethanol), wrapped in paper, and dried at 60 ° C to obtain terracotta 15.8 g, purity 93.7%.
  • Ion complexation neutralize pyridine in 40ml hydrochloric acid, stir rapidly, mix well, and let it stand for 60min, then filter and wash the filter cake with 300ml water to get acid water liquid 6 (constructed by filtrate + washing liquid, storage) and filter cake .
  • the filter cake was washed with water until it was acid free and drained.
  • the filter cake was rinsed with 200 ml of 50% ethanol, drained, and the filter cake was wrapped with paper, and dried at 60 ° C to obtain 32.1 g of olesin, which had a purity of 93.5%.
  • the filter cake was washed with water until it was acid free and drained.
  • the filter cake was rinsed with 100 ml of 50% ethanol, drained, and the filter cake was wrapped with paper, and dried at 60 ° C to obtain 15.4 g of olesin, which had a purity of 93.4%.
  • Method A add 500ml of warm water, quickly Stir until dissolved, quickly add 20 ml of phosphoric acid, stir rapidly, add 500 ml of water, mix well, and let it stand for 5 h, then filter by suction to obtain acid water solution 9. The filter cake was washed with water until it was acid free and drained.
  • the acid water solution 5 was taken, and subjected to 50 g of D101 macroporous adsorption resin column chromatography (intermediate by about 2 cm), and washed with 500 ml of water, and the acid water and the water washing liquid which were subjected to column chromatography were combined and placed in a 2000 ml round bottom flask, and 30 was added. 20 ml of hydrogen peroxide, placed in a sealed atmosphere overnight, precipitated iodine precipitate, siphoned the yellow supernatant, and then added 100 ml of water to the round bottom flask, suctioned with suction, and washed the round bottom flask with a small amount of water. The water washing solution was filtered together and washed 2-3 After that, sublimation at 150 ° C in a gas bath gave 5.9 g of iodine, which can be directly recycled.
  • the acid water solution 6 was taken through 100 g of D101 type macroporous adsorption resin column chromatography (intermediate by about 2 cm), and washed with 1000 ml of water, and the acid water and the water washing liquid which passed through column chromatography were combined, and placed in a 3000 ml round bottom flask, and added.

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Abstract

酚羟基黄酮类化合物半合成方法及碘回收方法，涉及A、B两种途径及碘回收，在A途径中黄酮溶于乙二醇或丙三醇的吡啶类溶剂中，以碘为脱氢剂、加热脱氢生成黄酮。在B途径中利用三价铝盐易与二氢黄酮类化合物络合，二氢黄酮或黄酮不溶于含醇的吡啶溶剂，采用三价铝和二氢黄酮络合，其络合及脱氢物在醇中溶解度大，以磷酸等脱铝剂分解络合物得到黄酮络合物，黄酮不溶于水，析出，滤过，即得产品。

Description

酚羟基黄酮类化合物半合成方法及碘回收方法 技术领域
本发明涉及酚羟基二氢黄酮类脱氢生成酚羟基黄酮类化合物半合成方法及碘回收方法，其领域属于化学、医药。
背景技术
含有酚羟基的二氢黄酮类化合物：由于天然二氢黄酮类化合物，系植物的次生代谢产物，分子中通常打入酶的标记，含有较多酚羟基，广泛存在自然界中，其含量丰富，提取工艺简单，价格低廉如90％橙皮苷市场价格每公斤约150元，98％柚皮苷市场价格每公斤约260元。但二氢黄酮类化合物药理作用不如黄酮类化合物明显，其原因系黄酮类化合物共轭结构强于二氢黄酮类化合物，前者在抗炎、抗氧化、抗自由基作用较后者好，如橙皮苷需要制备地奥司明，柚皮苷或柚皮素需要制备芹菜素等。
溴氧化法脱氢及缺点：二氢黄酮类化合物脱氢制备黄酮类化合物，其制备方法有溴氧化法和碘氧化法。在溴氧化法中，二氢黄酮分子中无裸露的酚羟基，可以直接使用液溴脱氢，其成本低廉。但如果有酚羟基，为避免溴代反应，其酚羟基则应先保护，如甲醚化、乙酰化，在该方法中存在保护、脱氢、去保护，致使步骤多，收率偏低，导致成本高。
碘氧化法脱氢及缺点：在碘氧化法中，分为NaI－DMSO(二甲基亚砜)或I2－DMSO高温氧化法和I2－吡啶等溶剂法。前者适合二氢黄酮分子中无裸露的酚羟基，以5,7,4'－三甲氧基柚皮素脱氢生成5,7,4'－三甲氧基芹菜素为例说明，在该法中，DMSO兼作溶剂及氧化剂，DMSO接近沸点的温度下，可以氧化碘离子到碘分子，而碘可以与二氢黄
Figure PCTCN2015073239-appb-000001
酮发生反应，使其脱氢，生成黄酮。碘虽然昂贵，但碘用量很少，其成本也很低 廉。含有酚羟基的二氢黄酮，因DMSO在高温下对酚羟基也有一定氧化，破坏黄酮母核，则不能使用NaI－DMSO(二甲基亚砜)或I2－DMSO高温氧化法，只能使I2－吡啶等溶剂法，一方面，因吡啶等溶剂不能氧化碘离子到碘分子，故碘的用量较大，导致成本高。另一方面黄酮类化合物的共平面性好于二氢黄酮类化合物，致使黄酮类化合物分子与分子更易于重叠排列，形成结晶，导致其在水和有机溶剂中溶解度变小，易于析出。因此，二氢黄酮类化合物脱氢产物较高或彻底脱氢，需要较多的有机溶剂。在常用的有机溶剂如吡啶、DMSO、DMF，其中DMSO的沸点为189℃，DMF的沸点为152℃，二者沸点较高，难于回收，通常作为一次性使用，导致成本偏高。再者，黄酮类化合物，如芹菜素、香叶木素在DMSO、DMF中溶解度有限，要使其溶解，就需要较多的DMSO、DMF。吡啶沸点为115℃，相较前两种可以回收，但也存在诸多问题：首先吡啶有碱性，易和黄酮分子中的酚羟基成盐，同时也和脱氢生成的碘化氢成盐，成盐后的吡啶，沸点显著增高。此外，由于吡啶环带π
Figure PCTCN2015073239-appb-000002
的环电子流，而黄酮因为酚羟基上的氧，存在P-π共轭效应，导致黄酮中的苯环带π
Figure PCTCN2015073239-appb-000003
的环电子流，产生π
Figure PCTCN2015073239-appb-000004
——π
Figure PCTCN2015073239-appb-000005
络合，使吡啶受到作用力增加，进一步加大吡啶回收的难度，吡啶回收率不高。以橙皮苷脱氢制备地奥司明为例，吡啶盐的两种形式及吡啶π
Figure PCTCN2015073239-appb-000006
——黄酮π
Figure PCTCN2015073239-appb-000007
络合作用，其反应式如下。另经过减压回收，吡啶的收率仅能达到70％，未回收的吡啶对环境有明显的污染。其次吡啶有恶臭的气味，在回收的过程中，对员工的身体有一定的损害。
Figure PCTCN2015073239-appb-000008
Figure PCTCN2015073239-appb-000009
酚羟基二氢黄酮类化合物脱氢例：对于含有酚羟基的二氢黄酮类化合物，因其种类繁多，如橙皮苷，柚皮苷、橙皮素、柚皮素等，每一种化合物的脱氢，均可举出数种方法，逐一列举困难较大，以橙皮苷制备地奥司明为代表性的说明碘－吡啶对含有酚羟基的二氢黄酮的现状。柑橘作物是全球仅次于小麦、玉米的世界第三大的贸易农产品，也是世界第一大水果。1978年之前，中国柑橘年产量稳定在30万吨左右，此后连年产量增加，2009年中国柑橘产量以2500万吨超过连续几十年占据世界第一的巴西。柑橘中含橙皮苷较丰富，如2010版中国药典·一部规定青皮含橙皮苷不得低于5.0％，陈皮含橙皮苷不得低于3.5％。大部分柑橘皮被浪费，仅少量作为陈皮和提取橙皮苷。地奥司明系橙皮苷脱氢产物，具有维生素P样作用，能降低血管脆性及异常的通透性，又用于防治高血压及动脉硬化的辅助治疗，用于治疗毛细血管脆性效果较芦丁、橙皮苷要强，而且具有毒性低的特点。用于治疗痔疮，慢性静脉功能不全等，年消耗量全球约4000吨，而且用量还在逐年增加。由于地奥司明在天然含量中较低，目前其制备方法系橙皮苷在碘的作用下脱氢生成。由于地奥司明不溶于水和大部分有机溶剂，故在橙皮苷制备地奥司明的工艺中，以吡啶为例，其用量通常达到橙皮苷的5倍量([1]高勇进.增强静脉张力性药物地奥司明合成进展研究[J].中国化工贸易，2013，(7)：226；[2]陈治宇.地奥司明合成工艺分析[J].中国科技纵横，2011，(7)：315；[3]李玉山，王经安.地奥司明的合成工艺[J].实验室研究与探索，2010，29(8)：39-41；[4]张光跃，张强.地奥司明的生产方法[P].中国，CN101089009A，2007.12.19)。阳水等采用微波辅助加热方法，以I2和NaI作催化剂，以K2C O3、NaOH的乙醇溶液和吡啶混合溶剂作为反应溶媒建立反应体系，将橙皮苷脱氢一步制备地奥司明。脱氢过程虽避免了高温和反应溶剂系统大量使用吡啶、二甲基亚砜等高沸点有毒溶剂，但用到较多甲醇、乙醇等有机溶剂、且后处理繁琐，地奥司明合成总收率在90％以下，工业化成本仍然偏高([5]阳水，刘毛东，雷国平，朱贞钰.一种符合EP7版质量标准的地奥司明原料药合成方法 [P].中国，CN102653549A，2012.09.05)。金海霞等一种地奥司明的生产系统，其特征在于，包括反应回收系统、中和过滤系统、粗品溶解过滤系统、半成品中和过滤系统、粉碎混合系统、碘回收系统、甲醇乙醇回收系统。在反应过程中，使用大量有机溶剂，且有机溶剂回收率仅能达到90％，对环境污染较大，步骤较多，其工业化成本依然较高。([6]金海霞，杨向农，赵劲松，王平.一种地奥司明的生产系统[P].中国，CN202011848U，2011.10.19)。
通过橙皮苷-I2-吡啶脱氢的例子可知，在碘－吡啶对酚羟基黄酮脱氢过程中，虽然条件较为温和，但存在吡啶用量大，难于回收，后处理复杂，收率偏低，导致产品成本偏高，如橙皮苷脱氢制备地奥司明。
发明内容
由鉴于此，依据含有酚羟基的黄酮类化合物与吡啶及其衍生物成盐，在醇的溶解度不同，设计A、B两种途径：A途径为黄酮类化合物在吡啶类溶剂中溶解度小，而在吡啶类和醇类混合溶剂中溶解度大；B途径为黄酮类化合物在吡啶类，或吡啶类与醇类混合溶剂中溶解度小，而且脱氢后，在100℃以上，并延长反应时间，尚能使黄酮苷类在脱氢的基础上，在直接脱糖生成黄酮苷元，如柚皮苷可以先脱氢、再脱糖直接制备芹菜素。A、B两种途径，较好的解决含有酚羟基二氢黄酮类化合物的脱氢存在吡啶用量大，后处理繁琐，产物收率较低的问题。如橙皮苷制备地奥司明为例，本发明所用的方法，与现有任何文献及专利相比，本发明法吡啶用量最低，后处理最简单，收率最高，绿色环保，易于工业化生产；有机溶剂用量少，碘在酸水液中溶解度小，易于回收，回收率高，易于工业化生产。柚皮苷可以一步法脱氢、脱糖直接制备芹菜素。故产品制备成本低廉。
在A途径(主要适合苷元，如柚皮素、橙皮素等)：吡啶类溶剂、酚羟基二氢黄酮类化合物、醇类溶剂、碘混合，搅拌，在20℃-180℃加热反应一段时间，形成均一溶液，TLC/HPLC/UV跟踪检查，加入少量保险酚或将反应产物快速加入含有保险粉的碱水中，搅拌溶解后，迅速加入酸水溶液，并搅拌均匀，密闭放置，析出黄酮沉淀，滤过(酸水液通过大孔吸附树脂除去少量黄酮后，以水洗涤，流出的酸水液及水洗涤液直接加双氧水，过夜，析出碘沉淀)，水洗涤滤饼至无酸性，抽干，然后烘干或晾干，即得黄酮类化合物；
在B途径(主要适合苷，如橙皮苷等)：加入三价铝离子化合物、迅速加入吡啶 类溶剂，迅速混合(防止三价铝离子化合物吸潮)，加入酚羟基二氢黄酮类化合物、醇类溶剂、碘混合，搅拌，在20℃-180℃加热反应一段时间，形成均一溶液，TLC/HPLC/UV跟踪检查，将反应产物快速加入水中，迅速搅拌溶解，迅速加入脱铝剂水溶液，盐酸等强酸中和吡啶，快速搅拌均匀，密闭放置，析出黄酮沉淀，滤过(酸水液通过大孔吸附树脂除去少量黄酮后，以水洗涤，流出的酸水液及水洗涤液直接加双氧水，过夜，析出碘沉淀)，水洗涤滤饼，抽干，以少量50％乙醇浸润滤饼(洗涤黄酮吸附少量碘)，并洗涤，抽干，然后烘干或晾干，即得黄酮类化合物；
碘回收：滤过酸水液及水洗涤液直接加双氧水，密闭放置(防止碘挥发)，过夜，析出碘沉淀，虹吸上清液(黄棕色)，剩余酸水液滤过，少量水洗涤碘滤饼，然后密闭升华即得碘。
本发明所说的含三价铝离子化合物，主要指三氯化铝、三溴化铝、三碘化铝、硫酸铝、硝酸铝、以及醇铝(甲醇铝、乙二醇铝、丙三醇铝等)等，其与二氢黄酮类化合物摩尔比例3：1-1：3，其中优选无水三氯化铝，其摩尔用量优选与二氢黄酮的摩尔量相等，与吡啶类溶剂优先混合溶解。
本发明所说的酚羟基二氢黄酮类化合物，主要指橙皮苷(CAS:520-26-3)、橙皮素-7-O-葡萄糖苷(CAS：31712-49-9)、橙皮素(CAS:520-33-2)、柚皮苷(CAS:10236-47-2)、柚皮素(CAS:480-41-1)，柚皮素-7-O-葡萄糖苷，圣草酚(CAS:552-58-9)等。
本发明所说的醇类溶剂，主要指甲醇、无水乙醇、丙醇、异丙醇、乙二醇、1,2－丙二醇、1,3－丙二醇、丙三醇，其中优选乙二醇和丙三醇，用量不限；优选甲醇，其体积用量不超过吡啶类溶剂体积(如吡啶10ml，甲醇体积最好不超过10ml，且若脱氢之后还要脱糖，其醇不能选多元甲醇，亦可不加醇)。
本发明所说的吡啶类溶剂，主要指吡啶、2－甲基吡啶、3-甲基吡啶、4－甲基吡啶、5－甲基吡啶、2，6－二甲基吡啶等。
本发明所说的脱铝剂，主要指各种酸及其盐类，可以是磷酸、磷酸二氢钠、磷酸氢二钠、保险粉、硫酸、盐酸、氢溴酸、醋酸、草酸、枸橼酸、酒石酸等，或任意两种极其以上混合使用，其中优选磷酸，其用量与三价铝摩尔比不低 于1：1。
本发明所说的酸，主要指各种酸，包括磷酸、硫酸、盐酸、氢溴酸、醋酸、草酸、枸橼酸、酒石酸等，或任意两种极其以上混合使用，其中优选磷酸、盐酸、硫酸。
本发明所说的黄酮，主要指含有酚羟基的黄酮，其代表性化合物：地奥司明(CAS:520-27-4)、野漆树苷(CAS:17306-46-6)、香叶木素(CAS:520-34-3)、香叶木素-7-O-葡萄糖苷(CAS：20126-59-4)、木犀草素(CAS:491-70-3)、芹菜素(CAS:520-36-5)，芹菜素β-D-7-O-葡萄糖苷(CAS:578-74-5)。
在A途径中，以二元醇或三元醇为脱氢溶剂，脱氢效果要好：以柚皮苷脱氢生成野漆树苷为例说明，当用甲醇－吡啶类溶剂，其产物为脱氢产物和碘代产物的混合物，当甲醇用量越少，脱氢产物越多，碘代产物越少；当用乙二醇－吡啶类溶剂或丙三醇－吡啶类溶剂时，得到脱氢产物，说明乙二醇或丙三醇可以作为溶剂。如果不用乙二醇、丙三醇等，仅以吡啶作为溶剂和除酸剂，则会大量析出沉淀，如柚皮素脱氢制备芹菜素，而且产物经过多次酸水洗涤，在烘干过程中，总有吡啶恶臭味；
Figure PCTCN2015073239-appb-000010
B途径中利用三价铝盐易和二氢黄酮类化合物络合，其络合物以及脱氢产物均易溶解在醇中，经过加热，形成均匀液体，不存在析出黄酮结晶的包合现象，故有吡啶用量特别少，该络合物极易被磷酸等脱铝剂分解生成磷酸铝等盐及黄酮类化合物。由于黄酮类化合物不溶于水，可以析出，滤过，即得；B法中，利用甲醇或多元醇可以溶解二氢黄酮类化合物、碘、吡啶及其衍生物，经过以碘脱氢生成的黄酮类化合物亦能溶解在多元醇中，加入酸中和吡啶，黄酮类化合物不溶于水，析出，滤过，即得；
曾用无水三氯化铝和橙皮素、柚皮素络合脱氢，但由于脱氢产物三氯化铝和香叶 木素或三氯化铝和芹菜素络合，其产物不溶于水，需多次处理或重结晶，才能获得较好的脱铝效果，其处理繁琐，不如A法处理简单。
在碘的回收方法中，碘形成不规则固体物和酸水液中吡啶、乙二醇、丙三醇、甲醇用量有关，有机溶剂用量越多，形成碘固体物速度也越慢，碘固体物也越少，故在碘脱氢过程中，吡啶、乙二醇、丙三醇、甲醇等试剂用量要少，当反应物不能形成均一溶液，可适当加入吡啶、乙二醇、丙三醇，使反应彻底，有机溶剂用量最少，碘回收率最高，创造最佳的效益；由于含有碘离子的酸水液尚含少量的黄酮，通过大孔吸附树脂如D101，可以除去酸水液中少量黄酮类化合物，再加双氧水，放置过夜，析出更高纯度的黑色碘。
在A途径中，以甲醇等一元醇与吡啶类溶剂构成混合溶剂，当甲醇等一元醇的体积大于吡啶类溶剂体积，则有碘代物生成。
吡啶及其衍生物为必须除酸剂：以柚皮苷为例，丙三醇或乙二醇作为溶剂，当以CaCO3作为除酸剂，水浴40℃以上，发生反应，并放出CO2气体，经检测主要得到碘代物，脱氢物不明显；当以吡啶及其衍生物作为除酸剂，主要得脱氢物，碘代物不明显，说明以二元醇或三元醇作为溶剂，吡啶类溶剂为必须除酸剂。
Figure PCTCN2015073239-appb-000011
本发明公开了含酚羟基二氢黄酮制备黄酮的方法，尤其4＝CO、5-OH二氢黄酮与三价铝络合在醇中脱氢制备黄酮、磷酸除黄酮铝络合物的方法，碘的快速回收方法，该方法尚能使苷类化合物脱糖，直接生成苷元，本领域技术人员可以借鉴本文内容，对不同含有酚羟基二氢黄酮类进行适当改进工艺参数，如调整溶剂的种类、用量、温度等而实现制备黄酮的方法。特别需要指出的是，各种含 有酚羟基的二氢黄酮类化合物脱氢制备黄酮的过程中，乙二醇或丙三醇作为溶剂，三价铝与黄酮络合起到增溶作用，磷酸起到破除黄酮与铝的络合作用的任一作用，它们都将被视为本发明所包括。相关人员明显不能在脱离本发明的内容、精神和范围对本文所述的方法、原理进行适当改动或变更与组合，来实现和应用本发明技术。
由于涉及含有酚羟基的二氢黄酮类类化合物，种类较多，数目众多。因此，不能对每一种苷类化合物进行举例说明，但为了进一步理解本发明，以A、B两种途径进行分类说明，实施例如下：
A途径，反应产物在吡啶类的二元醇或三元醇溶液中溶解度大，Al3+络合不是必须的：
实施例1
取95％橙皮素5g于250ml碘量瓶中，加入6ml吡啶、20ml乙二醇及4.2g碘，搅匀，水浴80℃密闭反应(或冷凝管上端加氯化钙的干燥管)。每1h搅拌1次，2h后呈均匀状液体，继续密闭反应6h。加入保险粉0.5g，搅拌均匀，迅速倾入300ml 1.5％NaOH溶液中，搅拌溶解后，加入盐酸调至酸性，密闭放置30min后，抽滤，得酸水液1(另器存放)和滤饼。水洗涤滤饼至无酸性，滤饼用50％乙醇碱水溶解，在用盐酸调至pH3-5，放置3h后滤过，滤饼用少量50％乙醇洗涤滤饼，60℃烘干，即得香叶木素4.62g，纯度96.2％。
Figure PCTCN2015073239-appb-000012
实施例2
取95％橙皮素5g于250ml碘量瓶中，加入2-甲基吡啶6ml、20ml丙三醇及4.2g碘，搅匀，水浴85℃密闭反应(或冷凝管上端加氯化钙的干燥管)，搅拌1次，1h后呈均匀状液体，继续密闭反应7h，加入保险粉0.5g，搅拌均匀，迅速倾入300ml 1.5％NaOH溶液中，搅拌溶解，迅速加入磷酸调至酸性，搅拌，密闭30min后，抽滤，得酸水液2(另器存放)和滤饼。水洗涤滤饼至无酸性，用少量50％乙醇洗涤滤饼，60℃烘干，即得香叶木素4.68g，纯度96.5％。
实施例3
取98％柚皮苷10g于250ml碘量瓶中，加入2-甲基吡啶5ml、20ml丙三醇及4.3g碘，搅匀，水浴80℃密闭反应(或冷凝管上端加氯化钙的干燥管)，每隔2h搅拌1次，8h后呈均匀状液体，加入保险粉0.5g，搅拌均匀，迅速倾入500ml水溶液中，搅拌溶解，加入磷酸调至酸性，密闭5h后，抽滤，得酸水液3(另器存放)和滤饼。水洗涤滤饼至无酸性，滤饼用少量50％乙醇浸润洗涤滤饼，60℃烘干，即得野漆树苷8.89g，纯度98.9％。
Figure PCTCN2015073239-appb-000013
实施例4
取98％柚皮素5.0g于250ml碘量瓶中，加入吡啶5ml、20ml乙二醇及4.7g碘，搅匀，水浴90℃密闭反应(或冷凝管上端加氯化钙的干燥管)，搅拌，1h后呈均匀状液体，再反应6h后，迅速倾入300ml 1.5％NaOH溶液中(含0.2％保险粉)，搅拌均匀，加入20％硫酸调至酸性，搅拌，30min后，抽滤，得酸水液4(另器存放)和滤饼。，水洗涤滤饼至无酸性，滤饼用少量50％乙醇浸润洗涤滤饼，60℃烘干，即得芹菜素4.46g，纯度98.8％。
Figure PCTCN2015073239-appb-000014
A途径，反应产物在吡啶的二元醇、三元醇或甲醇等一元醇溶液中溶解度小，需要三价铝络合进一步增溶：
实施例5
快速称取无水三氯化铝3.5g，迅速加入16ml吡啶混匀(冒出大量白烟，放出大量热)，加入92％橙皮苷16.5g，加入甲醇7ml，搅拌，再加入甲醇8ml，碘6.8g，搅拌，水浴80℃密闭反应(或冷凝管上端加氯化钙的干燥管)，每隔2h搅拌1次，4h后呈均匀糖浆状液体，再反应4h后，加入500ml温水，迅速搅拌至溶解，迅速加入磷酸20ml，盐酸16ml，迅速搅拌，拌匀，密闭放置60min后，抽滤，并用100ml水洗涤滤饼，得酸水液5(由滤液+洗涤液构成，另器存放)和滤饼。 再用水洗涤滤饼至无酸性并抽干，用100ml 50％乙醇润洗滤饼，抽干(50％乙醇可回收)，用纸包裹好，60℃烘干，即得土黄色地奥司明15.8g，纯度93.7％。
Figure PCTCN2015073239-appb-000015
实施例6
快速取无水三氯化铝7.0g，迅速加入2-甲基吡啶35ml，加入甲醇10ml，加入92％橙皮苷33g，碘13.5g，加入甲醇15ml，搅拌2min后，水浴80℃密闭反应(或冷凝管上端加氯化钙的干燥管)，每隔2h搅拌1次，4h后呈均匀糖浆状液体，再反应4h后，加入1000ml温水，迅速搅拌至溶解，迅速加入磷酸20ml破除黄酮与铝离子络合，40ml盐酸中和吡啶，迅速搅拌，拌匀，密闭放置60min后，抽滤并用300ml水洗涤滤饼，得酸水液6(由滤液+洗涤液构成，另器存放)和滤饼。再用水洗涤滤饼至无酸性并抽干。用200ml 50％乙醇润洗滤饼，抽干，用纸包裹好滤饼，60℃烘干，即得土黄色地奥司明32.1g，纯度93.5％。
实施例7
取无水三氯化铝3.5g，加入16ml吡啶，加入橙皮苷92％16.5g，加入乙二醇25ml，碘6.8g，水浴80℃密闭反应(或冷凝管上端加氯化钙的干燥管)，每隔2h搅拌1次，4h后呈均匀糖浆状液体，再反应4h后，加入500ml温水，迅速搅拌至溶解，迅速加入磷酸20ml，迅速搅拌，再加水500ml，拌匀，密闭放凉，抽滤，并用200ml水洗涤滤饼，得酸水液7和滤饼。水洗涤滤饼至无酸性并抽干。再用100ml50％乙醇润洗滤饼，抽干，用纸包裹好滤饼，60℃烘干，即得土黄色地奥司明15.4g，纯度93.4％。
实施例8
取无水三氯化铝3.5g，加入16ml吡啶，加入橙皮苷92％16.5g，加入丙三醇20ml， 加入碘6.8g，搅拌，水浴80℃形成均匀液体，密闭反应(或冷凝管上端加氯化钙的干燥管)，每隔2h搅拌1次，4h后呈均匀糖浆状液体，再反应4h后，加入500ml温水，迅速搅拌至溶解，迅速加入磷酸20ml，迅速搅拌，再加水500ml，拌匀，密闭放凉，抽滤，得酸水液8和滤饼。水洗涤滤饼至无酸性并抽干。再用100ml 50％乙醇润洗滤饼，抽干，用纸包裹好滤饼，60℃烘干，即得土黄色地奥司明15.6g，纯度93.3％。
实施例9柚皮苷制备野漆树苷和芹菜素
取无水三氯化铝3.5g，加入20ml吡啶混匀后，加入98％柚皮苷16.0g，加入甲醇10ml，碘7.0g，水浴80℃密闭反应(或冷凝管上端加氯化钙的干燥管)。每隔2h搅拌1次，4h后呈均匀糖浆状液体，再反应4h后完成脱氢，其后处理分为A法得野漆树苷和B法直接得芹菜素：A法：加入500ml温水，迅速搅拌至溶解，迅速加入磷酸20ml，迅速搅拌，再加水500ml，拌匀，密闭放置5h后，抽滤，得酸水液9。水洗涤滤饼至无酸性并抽干。再用100ml 50％乙醇润洗滤饼，抽干，用纸包裹好，60℃烘干，即得淡黄色野漆树苷14.7g，纯度98.2％；B法，补加吡啶15ml，搅匀，在气浴中120℃密闭蒸馏，TLC/HPLC跟踪至野漆树苷至完全生成芹菜素(约72h)，放冷，加入保险粉3.0g，搅拌5min，加入磷酸20ml，水50ml，加入盐酸30ml，搅拌均匀，加入水500ml，放置，析出芹菜素，抽滤，水洗涤，用纸包裹好，60℃烘干，水洗涤，即得黄色芹菜素7.35g，HPLC测定纯度为91.24％。
Figure PCTCN2015073239-appb-000016
Figure PCTCN2015073239-appb-000017
实施例10
取酸水液5，通过50g D101大孔吸附树脂柱层析(内经约2cm)，并用500ml水洗涤，合并通过柱层析的酸水液及水洗液，置于2000ml圆底烧瓶中，加入30％双氧水20ml，密闭放置过夜，析出碘沉淀，虹吸黄色的上清液，再向圆底烧瓶加入水100ml，抽滤，少量水洗涤圆底烧瓶，水洗涤液一并抽滤，洗涤2-3次，后于气浴中150℃升华，得碘5.9g，该碘可直接循环使用。
实施例11
取酸水液6，通过100g D101型大孔吸附树脂柱层析(内经约2cm)，并用1000ml水洗涤，合并通过柱层析的酸水液及水洗液，置于3000ml圆底烧瓶中，加入30％双氧水50ml，密闭放置过夜，析出碘沉淀，虹吸黄色上清液，再向圆底烧瓶加入水100ml，抽滤，少量水洗涤圆底烧瓶，水洗涤液一并抽滤，洗涤2-3次，后于气浴中150℃升华，得碘12.3g，该碘可直接循环使用。

Claims (8)

  1. 酚羟基黄酮类化合物半合成方法及碘回收方法：其具体特征在于A、B两种途径及碘的回收：
    A途径(主要适合苷元，如柚皮素、橙皮素等)：吡啶类溶剂、酚羟基二氢黄酮类化合物、醇类溶剂、碘混合，搅拌，在20℃-180℃加热反应一段时间，形成均一溶液，TLC/HPLC/UV跟踪检查，加入少量保险酚或将反应产物快速加入含有保险粉的碱水中，搅拌溶解后，迅速加入酸水溶液，并搅拌均匀，密闭放置，析出黄酮沉淀，滤过(酸水液通过大孔吸附树脂除去少量黄酮后，直接加双氧水，过夜，析出碘沉淀)，水洗涤滤饼至无酸性，抽干，然后烘干或晾干，即得黄酮类化合物；
    B途径(主要适合苷，如橙皮苷等)：加入三价铝离子化合物、迅速加入吡啶类溶剂，迅速混合(防止三价铝离子化合物吸潮)，加入酚羟基二氢黄酮类化合物、醇类溶剂、碘混合，搅拌，在20℃-180℃加热反应一段时间，形成均一溶液，TLC/HPLC/UV跟踪检查，将反应产物快速加入水中，迅速搅拌溶解，迅速加入脱铝剂水溶液，盐酸等强酸中和吡啶，快速搅拌均匀，密闭放置，析出黄酮沉淀，滤过(酸水液直接加双氧水，析出碘沉淀)，水洗涤滤饼，抽干，以少量50％乙醇浸润滤饼(洗涤黄酮吸附少量碘)，并洗涤，抽干，然后烘干或晾干，即得黄酮类化合物；
    碘回收：滤过酸水液通过大孔吸附树脂，并用水洗涤，合并酸水液及水洗涤液，直接加双氧水，密闭放置过夜，析出碘沉淀，虹吸上清液(黄棕色)，剩余酸水液滤过，少量水洗涤碘滤饼，将碘的固体密闭升华即得碘。
  2. 如权利要求1所述的方法，其特征在于所说三价铝离子化合物，主要指三氯化铝、三溴化铝、三碘化铝、硫酸铝、硝酸铝、以及醇铝(甲醇铝、乙二醇铝、丙三醇铝等)等，其与二氢黄酮类化合物摩尔比例3：1-1：3，其中优选无水三氯化铝，其摩尔用量优选与二氢黄酮的摩尔量相等，与吡啶类溶剂优先混合溶解。
  3. 如权利要求1所述的方法，其特征在于醇类溶剂，主要指甲醇、无水乙醇、丙醇、异丙醇、乙二醇、1,2－丙二醇、1,3－丙二醇、丙三醇，其中优选乙二醇和丙三醇，用量不限；优选甲醇，其体积用量不超过吡啶类溶剂体积(如吡啶10ml，甲醇体积最好不超过10ml，且若脱氢之后还要脱糖，其醇不能选多元甲醇，亦可不加醇)。
  4. 如权利要求1所述的方法，其特征在于吡啶类溶剂，主要指吡啶、2－甲基吡啶、3-甲基吡啶、4－甲基吡啶、5－甲基吡啶、2，6－二甲基吡啶等。
  5. 如权利要求1所述的方法，其特征在脱铝剂，主要指各种酸及其盐类，可以是磷酸、磷酸二氢钠、磷酸氢二钠、保险粉、硫酸、盐酸、氢溴酸、醋酸、草酸、枸橼酸、酒石酸等，或任意两种极其以上混合使用，其中优选磷酸，其用量与三价铝摩尔比不低于1：1。
  6. 如权利要求1所述的方法，其特征在于酸，主要指各种酸，包括磷酸、硫酸、盐酸、氢溴酸、醋酸、草酸、枸橼酸、酒石酸等，或任意两种极其以上混合使用，其中优选磷酸、盐酸、硫酸。
  7. 如权利要求1所述的方法，其特征在于酚羟基二氢黄酮类化合物，主要指橙皮苷(CAS:520-26-3)、橙皮素-7-O-葡萄糖苷(CAS：31712-49-9)、橙皮素(CAS:520-33-2)、柚皮苷(CAS:10236-47-2)、柚皮素(CAS:480-41-1)，柚皮素-7-O-葡萄糖苷，圣草酚(CAS:552-58-9)等。
  8. 如权利要求1所述的方法，其特征在于黄酮，主要指含有酚羟基的黄酮，其代表性化合物：地奥司明(CAS:520-27-4)、野漆树苷(CAS:17306-46-6)、香叶木素(CAS:520-34-3)、香叶木素-7-O-葡萄糖苷(CAS：20126-59-4)、木犀草素(CAS:491-70-3)、芹菜素(CAS:520-36-5)，芹菜素β-D-7-O-葡萄糖苷(CAS:578-74-5)。
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