CN105732744A - Method for preparing green and economic diosmin - Google Patents
Method for preparing green and economic diosmin Download PDFInfo
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- CN105732744A CN105732744A CN201610279655.6A CN201610279655A CN105732744A CN 105732744 A CN105732744 A CN 105732744A CN 201610279655 A CN201610279655 A CN 201610279655A CN 105732744 A CN105732744 A CN 105732744A
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- 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
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- C01B7/00—Halogens; Halogen acids
- C01B7/13—Iodine; Hydrogen iodide
- C01B7/14—Iodine
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The invention discloses a method for preparing green and economic diosmin. The method comprises three main steps of preparation, recycling and refining. Compared with a conventional method, the method thoroughly avoids use of pyridine and inorganic base, the production environment is greatly improved, the aftertreatment is simple, iodine and solvents can be recycled, the reaction conditions are gentle, the production cost is low, and meanwhile in the method, a crude product is not refined in a classic alkali solution acidification mode instead of a mode that diosmin is separated out, then the purity of a finished product can be up to 99%, the product quality can be improved, and moreover the method is simple and convenient to operate and applicable to industrial production.
Description
Technical field
The preparation method that the present invention relates to a kind of medicine, particularly to the preparation method of a kind of diosmin.
Background technology
Diosmin, chemical name is 7-{ [6-O-(6-deoxidation-α-L-mannose)-β-D-Glucopyranose .] oxygen base }-5-hydroxyl-2-(3-hydroxyl-4-methoxybenzene)-4H-L-benzopyran-4-one, it is a kind of lark or faint yellow draws moist powder, it is dissolved in dimethyl sulfoxide, diluted sodium hydroxide solution, being practically insoluble in ethanol (96%) and water, its structure is as follows:
Diosmin has Citrin sample effect, can reduce the permeability of vascular fragility and exception, can be used for preventing and treating the auxiliary treatment of hypertension and arteriosclerosis, is used for treating capillary fragility effect relatively rutin, Hesperidin is eager to excel, and is had the advantages that toxicity is low.It can also reduce blood viscosity, strengthen erythrocytic flow velocity, thus it is stagnant to reduce the microcirculatory stasis of blood, this product is mainly used in treatment chronic venous insufficiency clinically.
Diosmin content in natural product is considerably less, and the cost of extracting directly is high, and industrial is all prepare diosmin by the mode of oxidation Hesperidin, as follows:
Present stage, the method producing diosmin by aoxidizing Hesperidin mainly has three kinds: bromo dehydrogenation, NBS dehydrogenation and iodo dehydrogenation.Bromo dehydrogenation needs two-step reaction, and technique is loaded down with trivial details, and bromine is relatively big to producers' actual bodily harm, and labor protection is relatively costly；By NBS to the Hesperidin Oxidative Dehydrogenation relatively complicated complexity of technique for diosmin, and NBS is expensive, it is impossible to realizing it and recycle, production cost is higher, and both approaches has not been suitable for industrialized production at present.
The method of iodo dehydrogenation, compared to first two method, technique is simple, the reagent iodine used is comparatively gentle and can realize recycling, there is certain advantage, but this type of method that nearly all report is out all employ pyridine or dimethylformamide as reaction dissolvent, especially based on pyridine.Owing to pyridine has strong impulse abnormal smells from the patient, human body is had bigger toxic action, therefore in process of production that the harm of environment and operator is bigger.Simultaneously because pyridine, dimethylformamide are difficult to eliminate as solvent in last handling process, thus resulting in product dissolvent residual too high, product quality is difficult to ensure that.
Recently, use pyridine as far as possible on a small quantity and avoid the Main way using high boiling solvent dimethylformamide to become this process modification.Patent CN102653549 discloses the synthetic method that a kind of diosmin is new, and this invention adopts Microwave-assisted firing method, with I2It is dehydrating agent with NaI, with K2CO3, the alcoholic solution of NaOH and pyridine mixed solvent set up reaction system as action solvent, thus de-for Hesperidin hydroformylation step is prepared diosmin.The method reduces the consumption of pyridine really, but the method needs the auxiliary of microwave, does not therefore have the feasibility of industry amplification.And even with a small amount of pyridine, due to pyridine strong impulse, also the health of operator can be caused bigger injury.
The method of patent CN102875621 report is by making Hesperidin, iodine, inorganic alkaline agents and organic solvent are mixed and heated to 80～100 DEG C and prepare diosmin, the method completely avoid the use of pyridine, production environment is greatly improved, but the alkali-soluble acid analysis method of routine is adopted equally due to post processing, product purity only about 95%, the mixed solvent used also is unfavorable for the recovery of solvent, and due to inorganic base and iodine generation dismutation reaction in reaction, iodine is caused to be difficult to reclaim, thus increasing production cost, which also limits this invention application in large-scale production.
To sum up we can see that, although the method preparing diosmin has been achieved for incremental advances, but for current preparation method, three below aspect is mainly had to require further improvement: one is the use avoiding pyridine and high boiling solvent, improve production environment, reduce energy consumption, it is achieved solvent recovery is applied mechanically, reduce cost；Two is explore more efficient purification diosmin technique, improves product quality；Three response rate being an up iodine, improve technique, reduce the impurity that Hesperidin at high temperature produces further.
Summary of the invention
In view of this, the preparation method that the present invention provides a kind of diosmin, it can get rid of the use of pyridine or high boiling solvent completely, adopt a kind of brand-new thinking purification diosmin crude product, thus preparing the high-quality diosmin finished product of high-purity, and solvent and iodine can realize recycling, it is achieved that the preparation method of a kind of diosmin green economy.
It is an object of the invention to be achieved through the following technical solutions, comprise the following steps:
Preparation process: adding Hesperidin, iodine in organic basic solvent, heating, to 40～50 DEG C, makes Hesperidin dissolve, then is warming up to 60～90 DEG C, and HPLC detects reaction end；
Recycling step: distillation reaction solution, reclaims organic basic solvent, and distillation adds purified water, stirring after terminating, regulate pH to 5～7, stand crystallize, filter, obtain diosmin crude product, adds hydrogen peroxide and dilute hydrochloric acid reclaims iodine in filtrate；
Purification step: with sodium hydrate aqueous solution by dissolving crude product, filter, take filtrate, in filtrate, add water-miscible organic solvent precipitated out by the diosmin after one-tenth salt, again by the diosmin water dissolution after one-tenth salt, regulate pH to 5～7, stand crystallize, filter, dry, pulverize, obtain diosmin finished product.
Wherein organic basic solvent described in preparation process is the one in morpholine, N-methylmorpholine, DIPEA, triethylamine, N-methyl piperidine, hexahydropyridine, and organic basic solvent and Hesperidin mass ratio are 1: 3～1 6；
The purified water volume wherein added in recycling step is 1～2 times of reaction dissolvent volume.
Wherein in recycling step the quality of the quality of hydrogen peroxide and Hesperidin for ratio for 1～3: 10～20, it is preferred to 1～3: 5～10；The mass ratio of sodium hydroxide quality and Hesperidin is 1: 4～20, it is preferred to 1: 4～7.
Wherein the water-miscible organic solvent in purification step is the one in methanol, ethanol, acetonitrile, acetone, isopropanol, oxolane, and its addition volume is 1.5～3 times of crude product aqueous solution volume.
The weight wherein adding water in purification step is 12～18 times of Hesperidin weight, and the temperature of forced air drying is 70～90 DEG C.
Present invention have the advantage that
1) reaction of Hesperidin and iodine avoids the use of inorganic base, improves the response rate of iodine；Under 40-50 DEG C of condition, carry out iodine replacement, reduce Hesperidin high temperature impurity content；
2) improvement of diosmin process for refining, substantially increases the purity of diosmin final finished, improves the quality of medicine.
Detailed description of the invention
In order to make those skilled in the art be more fully understood that technical scheme, below in conjunction with specific embodiment, the present invention is described in further detail, and these descriptions are not that present invention is further limited.It should be understood by those skilled in the art that the equivalent replacement that the technical characteristic to the present invention is made, or be correspondingly improved, still fall within protection scope of the present invention.
Embodiment 1
20L reactor adds Hesperidin 2kg, iodine 0.92kg, it is subsequently adding morpholine 8L, start stirring and heat up, treat that temperature rises to 40 DEG C of samples and is completely dissolved, it is incubated 0.5 hour at 45 DEG C ± 5 DEG C, then improves temperature to 70 DEG C ± 5 DEG C insulated and stirred 1.5～3 hours (HPLC monitors after Hesperidin converts completely and is decided to be reaction end).Recycling design to reactant becomes thick, add 12L purified water, stirring, by feed liquid press-in reaction surge tank after stirring evenly, adds hydrochloric acid adjustment pH=5～7 and carries out crystallization, filter, obtain filter cake and filtrate, add hydrochloric acid and regulate filtrate pH=2, be slowly added to 30% hydrogen peroxide 0.41kg, filter, reclaim iodine.Filter cake massive laundering is washed, and obtains diosmin crude product.nullPurification dissolving tank will add purified water 12L and 0.39kg sodium hydroxide，Stir, after being completely dissolved, diosmin crude product is added continuation stirring to being completely dissolved，Now it is slowly added to 20L oxolane，Solid is made to precipitate out，Filter，Take filter cake (purity of diosmin sodium salt is 99.13%)，Again purification dissolving tank will add purified water 30L，Then filter cake is added stirring to being completely dissolved，PH=5～7 are now slowly regulated with dilute hydrochloric acid，A large amount of solid is had to precipitate out，Filter，Filter cake large-scale purification water washing 1 hour，Collect filter cake，Put into 80 DEG C ± 5 DEG C forced air dryings，Pulverize，Obtain diosmin finished product 1.69kg,Purity is 99.34%，Yield is 85.7%，Solvent recovering rate is 80.2%，The iodine response rate is 85.8%，Dissolvent residual、Related impurities is all up to standard.
Embodiment 2
20L reactor adds Hesperidin 2kg, iodine 0.92kg, it is subsequently adding N-methylmorpholine 10L, start stirring and heat up, treat that temperature rises to 40 DEG C of samples and is completely dissolved, it is incubated 0.5 hour at 45 DEG C ± 5 DEG C, then improves temperature to 80 DEG C ± 5 DEG C insulated and stirred 1.5～3 hours (HPLC monitors after Hesperidin converts completely and is decided to be reaction end).Recycling design to reactant becomes thick, adds 12L purified water, by feed liquid press-in reaction surge tank after stirring evenly, adds hydrochloric acid adjustment pH=5～7 and carries out crystallization, filter, obtain filter cake and filtrate, add hydrochloric acid and regulate filtrate pH=2, it is slowly added to 30% hydrogen peroxide 0.41kg, filters, reclaim iodine.Filter cake massive laundering is washed, and obtains diosmin crude product.nullPurification dissolving tank will add purified water 12L and 0.39kg sodium hydroxide，Stir, after being completely dissolved, diosmin crude product is added continuation stirring to being completely dissolved，Now it is slowly added to 20L oxolane，Solid is made to precipitate out，Filter，Take filter cake (purity of diosmin sodium salt is 99.01%)，Again purification dissolving tank will add purified water 30L，Then filter cake is added stirring to being completely dissolved，PH=5～7 are now slowly regulated with dilute hydrochloric acid，A large amount of solid is had to precipitate out，Filter，Filter cake large-scale purification water washing 1 hour，Collect filter cake，Put into 80 DEG C ± 5 DEG C forced air dryings，Pulverize，Obtain diosmin finished product 1.65kg,Purity is 99.13%，Yield is 82.9%，Solvent recovering rate is 84.2%，The iodine response rate is 88.6%，Dissolvent residual、Related impurities is all up to standard.
Embodiment 3
20L reactor adds Hesperidin 2kg, iodine 0.92kg, it is subsequently adding N, N-diisopropylethylamine 12L, start stirring and heat up, treat that temperature rises to 40 DEG C of samples and is completely dissolved, be incubated 0.5 hour at 45 DEG C ± 5 DEG C, then improve temperature to 80 DEG C ± 5 DEG C insulated and stirred 1.5～3 hours (HPLC monitors after Hesperidin converts completely and is decided to be reaction end).Recycling design to reactant becomes thick, adds 12L purified water, by feed liquid press-in reaction surge tank after stirring evenly, adds hydrochloric acid adjustment pH=5～7 and carries out crystallization, filter, obtain filter cake and filtrate, add hydrochloric acid and regulate filtrate pH=2, it is slowly added to 30% hydrogen peroxide 0.41kg, filters, reclaim iodine.Filter cake massive laundering is washed, and obtains diosmin crude product.nullPurification dissolving tank will add purified water 12L and 0.39kg sodium hydroxide，Stir, after being completely dissolved, diosmin crude product is added continuation stirring to being completely dissolved，Now it is slowly added to 20L oxolane，Solid is made to precipitate out，Filter，Take filter cake (purity of diosmin sodium salt is 99.18%)，Again purification dissolving tank will add purified water 30L，Then filter cake is added stirring to being completely dissolved，PH=5～7 are now slowly regulated with dilute hydrochloric acid，A large amount of solid is had to precipitate out，Filter，Filter cake large-scale purification water washing 1 hour，Collect filter cake，Put into 80 DEG C ± 5 DEG C forced air dryings，Pulverize，Obtain diosmin finished product 1.63kg,Purity is 99.33%，Yield is 81.9%，Solvent recovering rate is 75.2%，The iodine response rate is 74.6%，Dissolvent residual、Related impurities is all up to standard.
Embodiment 4
20L reactor adds Hesperidin 2kg, iodine 0.92kg, it is subsequently adding triethylamine 9L, start stirring and heat up, treat that temperature rises to 40 DEG C of samples and is completely dissolved, it is incubated 0.5 hour at 45 DEG C ± 5 DEG C, then improves temperature to 70 DEG C ± 5 DEG C insulated and stirred 1.5～3 hours (HPLC monitors after Hesperidin converts completely and is decided to be reaction end).Recycling design to reactant becomes thick, add 12L purified water, stirring, by feed liquid press-in reaction surge tank after stirring evenly, adds hydrochloric acid adjustment pH=5～7 and carries out crystallization, filter, obtain filter cake and filtrate, add hydrochloric acid and regulate filtrate pH=2, be slowly added to 30% hydrogen peroxide 0.41kg, filter, reclaim iodine.Filter cake massive laundering is washed, and obtains diosmin crude product.nullPurification dissolving tank will add purified water 12L and 0.39kg sodium hydroxide，Stir, after being completely dissolved, diosmin crude product is added continuation stirring to being completely dissolved，Now it is slowly added to 20L oxolane，Solid is made to precipitate out，Filter，Take filter cake (purity of diosmin sodium salt is 99.01%)，Again purification dissolving tank will add purified water 30L，Then filter cake is added stirring to being completely dissolved，PH=5～7 are now slowly regulated with dilute hydrochloric acid，A large amount of solid is had to precipitate out，Filter，Filter cake large-scale purification water washing 1 hour，Collect filter cake，Put into 80 DEG C ± 5 DEG C forced air dryings，Pulverize，Obtain diosmin finished product 1.67kg,Purity is 99.15%，Yield is 83.9%，Solvent recovering rate is 84.0%，The iodine response rate is 90.1%，Dissolvent residual、Related impurities is all up to standard.
Embodiment 5
20L reactor adds Hesperidin 2kg, iodine 0.92kg, it is subsequently adding N-methyl piperidine 6L, start stirring and heat up, treat that temperature rises to 40 DEG C of samples and is completely dissolved, it is incubated 0.5 hour at 45 DEG C ± 5 DEG C, then improves temperature to 70 DEG C ± 5 DEG C insulated and stirred 1.5～3 hours (HPLC monitors after Hesperidin converts completely and is decided to be reaction end).Recycling design to reactant becomes thick, add 12L purified water, stirring, by feed liquid press-in reaction surge tank after stirring evenly, adds hydrochloric acid adjustment pH=5～7 and carries out crystallization, filter, obtain filter cake and filtrate, add hydrochloric acid and regulate filtrate pH=2, be slowly added to 30% hydrogen peroxide 0.41kg, filter, reclaim iodine.Filter cake massive laundering is washed, and obtains diosmin crude product.nullPurification dissolving tank will add purified water 12L and 0.39kg sodium hydroxide，Stir, after being completely dissolved, diosmin crude product is added continuation stirring to being completely dissolved，Now it is slowly added to 20L oxolane，Solid is made to precipitate out，Filter，Take filter cake (purity of diosmin sodium salt is 99.10%)，Again purification dissolving tank will add purified water 30L，Then filter cake is added stirring to being completely dissolved，PH=5～7 are now slowly regulated with dilute hydrochloric acid，A large amount of solid is had to precipitate out，Filter，Filter cake large-scale purification water washing 1 hour，Collect filter cake，Put into 80 DEG C ± 5 DEG C forced air dryings，Pulverize，Obtain diosmin finished product 1.66kg,Purity is 99.22%，Yield is 83.4%，Solvent recovering rate is 84.3%，The iodine response rate is 85.7%，Dissolvent residual、Related impurities is all up to standard.
Embodiment 6
20L reactor adds Hesperidin 2kg, iodine 0.92kg, it is subsequently adding hexahydropyridine 12L, start stirring and heat up, treat that temperature rises to 40 DEG C of samples and is completely dissolved, it is incubated 0.5 hour at 45 DEG C ± 5 DEG C, then improves temperature to 80 DEG C ± 5 DEG C insulated and stirred 1.5～3 hours (HPLC monitors after Hesperidin converts completely and is decided to be reaction end).Recycling design to reactant becomes thick, add 12L purified water, stirring, by feed liquid press-in reaction surge tank after stirring evenly, adds hydrochloric acid adjustment pH=5～7 and carries out crystallization, filter, obtain filter cake and filtrate, add hydrochloric acid and regulate filtrate pH=2, be slowly added to 30% hydrogen peroxide 0.41kg, filter, reclaim iodine.Filter cake massive laundering is washed, and obtains diosmin crude product.nullPurification dissolving tank will add purified water 12L and 0.39kg sodium hydroxide，Stir, after being completely dissolved, diosmin crude product is added continuation stirring to being completely dissolved，Now it is slowly added to 20L oxolane，Solid is made to precipitate out，Filter，Take filter cake (purity of diosmin sodium salt is 99.21%)，Again purification dissolving tank will add purified water 30L，Then filter cake is added stirring to being completely dissolved，PH=5～7 are now slowly regulated with dilute hydrochloric acid，A large amount of solid is had to precipitate out，Filter，Filter cake large-scale purification water washing 1 hour，Collect filter cake，Put into 80 DEG C ± 5 DEG C forced air dryings，Pulverize，Obtain diosmin finished product 1.69kg,Purity is 99.31%，Yield is 85.7%，Solvent recovering rate is 82.2%，The iodine response rate is 87.5%，Dissolvent residual、Related impurities is all up to standard.
Embodiment 7
20L reactor adds Hesperidin 2kg, iodine 0.92kg, it is subsequently adding morpholine 10L, start stirring and heat up, treat that temperature rises to 40 DEG C of samples and is completely dissolved, it is incubated 0.5 hour at 45 DEG C ± 5 DEG C, then improves temperature to 80 DEG C ± 5 DEG C insulated and stirred 1.5～3 hours (HPLC monitors after Hesperidin converts completely and is decided to be reaction end).Recycling design to reactant becomes thick, add 12L purified water, stirring, by feed liquid press-in reaction surge tank after stirring evenly, adds hydrochloric acid adjustment pH=5～7 and carries out crystallization, filter, obtain filter cake and filtrate, add hydrochloric acid and regulate filtrate pH=2, be slowly added to 30% hydrogen peroxide 0.41kg, filter, reclaim iodine.Filter cake massive laundering is washed, and obtains diosmin crude product.nullPurification dissolving tank will add purified water 12L and 0.39kg sodium hydroxide，Stir, after being completely dissolved, diosmin crude product is added continuation stirring to being completely dissolved，Now it is slowly added to 20L isopropanol，Solid is made to precipitate out，Filter，Take filter cake (purity of diosmin sodium salt is 99.18%)，Again purification dissolving tank will add purified water 30L，Then filter cake is added stirring to being completely dissolved，PH=5～7 are now slowly regulated with dilute hydrochloric acid，A large amount of solid is had to precipitate out，Filter，Filter cake large-scale purification water washing 1 hour，Collect filter cake，Put into 80 DEG C ± 5 DEG C forced air dryings，Pulverize，Obtain diosmin finished product 1.69kg,Purity is 99.28%，Yield is 85.7%，Solvent recovering rate is 82.2%，The iodine response rate is 90.5%，Dissolvent residual、Related impurities is all up to standard.
Embodiment 8
20L reactor adds Hesperidin 2kg, iodine 0.92kg, it is subsequently adding morpholine 12L, start stirring and heat up, treat that temperature rises to 40 DEG C of samples and is completely dissolved, it is incubated 0.5 hour at 45 DEG C ± 5 DEG C, then improves temperature to 70 DEG C ± 5 DEG C insulated and stirred 1.5～3 hours (HPLC monitors after Hesperidin converts completely and is decided to be reaction end).Recycling design to reactant becomes thick, add 12L purified water, stirring, by feed liquid press-in reaction surge tank after stirring evenly, adds hydrochloric acid adjustment pH=5～7 and carries out crystallization, filter, obtain filter cake and filtrate, add hydrochloric acid and regulate filtrate pH=2, be slowly added to 30% hydrogen peroxide 0.41kg, filter, reclaim iodine.Filter cake massive laundering is washed, and obtains diosmin crude product.nullPurification dissolving tank will add purified water 12L and 0.39kg sodium hydroxide，Stir, after being completely dissolved, diosmin crude product is added continuation stirring to being completely dissolved，Now it is slowly added to 20L acetonitrile，Solid is made to precipitate out，Filter，Take filter cake (purity of diosmin sodium salt is 99.27%)，Again purification dissolving tank will add purified water 30L，Then filter cake is added stirring to being completely dissolved，PH=5～7 are now slowly regulated with dilute hydrochloric acid，A large amount of solid is had to precipitate out，Filter，Filter cake large-scale purification water washing 1 hour，Collect filter cake，Put into 80 DEG C ± 5 DEG C forced air dryings，Pulverize，Obtain diosmin finished product 1.69kg,Purity is 99.44%，Yield is 85.7%，Solvent recovering rate is 80.1%，The iodine response rate is 89.6%，Dissolvent residual、Related impurities is all up to standard.
In order to make those skilled in the art be more fully understood that technical scheme, design reference examples below in conjunction with the inventive method (CN102875621) reported, to embody the advantage of the present invention better.
Embodiment 9 comparative example 1
20L reactor adds Hesperidin 2kg, iodine 0.94kg, sodium hydroxide 0.24kg, being eventually adding morpholine: the mixed solvent 16L of water (60:40), be evenly stirred until and be completely dissolved, heating is to 85～90 DEG C, insulated and stirred 9 hours, reactant liquor becomes thick liquid.Add 60 grams of sodium thiosulfate, under vacuum 85～90 DEG C of recycling design.After solvent recovery is complete, adds 16L purified water, stir, filter, collect waste liquid, reclaim iodine.Filter cake is washed, and obtains diosmin crude product.Diosmin crude product 16L and the 0.6kg sodium hydroxide that adds water makes it be completely dissolved, and high speed centrifuge filters, and takes filtrate.Add water 14L in filtrate, and slowly adding sulfuric acid acidation pH is 2～3, stands, and filters, and washing obtains diosmin coarse crystallization.Coarse crystallization add water 16L and 0.6kg sodium hydroxide stirring be completely dissolved after, put into crystallizer, add water 14L, slowly adding sulfuric acid acidation pH is 2～3, stands, filters, washes, dries, pulverizes, obtains diosmin finished product 1.62kg, purity is 94.34%, yield is 81.4%, and solvent recovering rate is 72.3%, and the iodine response rate is 60.3%.
Embodiment 10 comparative example 2
20L reactor adds Hesperidin 2kg, iodine 0.94kg, sodium hydroxide 0.24kg, being eventually adding morpholine: the mixed solvent 16L of methanol (60:40), be evenly stirred until and be completely dissolved, heating is to 85～90 DEG C, insulated and stirred 9 hours, reactant liquor becomes thick liquid.Add 60 grams of sodium thiosulfate, under vacuum 85～90 DEG C of recycling design.After solvent recovery is complete, adds 16L purified water, stir, filter, collect waste liquid, reclaim iodine.Filter cake is washed, and obtains diosmin crude product.Diosmin crude product 16L and the 0.6kg sodium hydroxide that adds water makes it be completely dissolved, and high speed centrifuge filters, and takes filtrate.Add water 14L in filtrate, and slowly adding sulfuric acid acidation pH is 2～3, stands, and filters, and washing obtains diosmin coarse crystallization.Coarse crystallization add water 16L and 0.6kg sodium hydroxide stirring be completely dissolved after, put into crystallizer, add water 14L, slowly adding sulfuric acid acidation pH is 2～3, stands, filters, washes, dries, pulverizes, obtains diosmin finished product 1.64kg, purity is 94.12%, yield is 82.4%, and solvent recovering rate is 70.3%, and the iodine response rate is 58.5%.
Embodiment 11
By the diosmin highly finished product obtained by embodiment 1-10, adopting HPLC to detect its purity, concrete detection method is as follows:
It is filler (PhenomenexC18,4.6mm*100mm, 3um or the suitable chromatographic column of usefulness) with octadecylsilane chemically bonded silica；With water-methanol-glacial acetic acid-acetonitrile (66:28:6:2) for mobile phase, detection wavelength is 275nm, takes sensitivity solution 10ul and injects chromatograph of liquid, and the signal to noise ratio of main constituent peak height should be greater than 10；Precision measures reference substance solution and each 10ul of need testing solution again, is injected separately into chromatograph of liquid, and record chromatogram is to 5 times of main peak retention time.
Containing following three kinds of impurity in diosmin finished product, it is the different Radix seu Folium Tosicodendri Delavayi glucoside of impurity A respectively, impurity B diosmetin, impurity C linarin, its structure is as follows:
Testing result refers to following table:
Table 1 embodiment 1-10 diosmin finished product HPLC testing result
Claims (7)
1. the diosmin preparation method of a green economy, it is characterised in that being made up of preparation, recovery, refining three big steps, concrete preparation method is as follows:
Preparation process: adding Hesperidin, iodine in organic basic solvent, heating, to 40～50 DEG C, makes Hesperidin dissolve, then is warming up to 60～90 DEG C, and HPLC detects reaction end；
Recycling step: distillation reaction solution, reclaims organic basic solvent, and distillation adds purified water, stirring after terminating, regulate pH to 5～7, stand crystallize, filter, obtain diosmin crude product, adds hydrogen peroxide and dilute hydrochloric acid reclaims iodine in filtrate；
Purification step: with sodium hydrate aqueous solution by dissolving crude product, filter, take filtrate, in filtrate, add water-miscible organic solvent precipitated out by the diosmin after one-tenth salt, again by the diosmin water dissolution after one-tenth salt, regulate pH to 5～7, stand crystallize, filter, dry, pulverize, obtain diosmin finished product.
2. the diosmin preparation method of a kind of green economy according to claim 1, it is characterized in that: organic basic solvent described in preparation process is morpholine, N-methylmorpholine, N, one in N-diisopropylethylamine, triethylamine, N-methyl piperidine, hexahydropyridine, organic basic solvent and Hesperidin mass ratio are 1: 3～1 6.
3. the diosmin preparation method of a kind of green economy according to claim 1, it is characterised in that: the purified water volume added in recycling step is 1～2 times of reaction dissolvent volume.
4. the diosmin preparation method of a kind of green economy according to claim 1, it is characterised in that: the quality of recycling step hydrogen peroxide and the quality of Hesperidin for ratio for 1～3: 10～20；The mass ratio of sodium hydroxide quality and Hesperidin is 1: 4～20.
5. the diosmin preparation method of a kind of green economy according to claim 4, it is characterised in that: the quality of hydrogen peroxide and the quality of Hesperidin are for ratio for 1～3: 5～10, and the mass ratio of sodium hydroxide quality and Hesperidin is 1: 4～7.
6. the diosmin preparation method of a kind of green economy according to claim 1, it is characterized in that: the water-miscible organic solvent added in purification step is the one in methanol, ethanol, acetonitrile, acetone, isopropanol, oxolane, and the volume of addition is 1.5～3 times of crude product aqueous solution volume.
7. the diosmin preparation method of a kind of green economy according to claim 1, it is characterised in that: it is 12～18 times of Hesperidin weight that purification step adds the weight of water, and the temperature of forced air drying is 70～90 DEG C.
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