CN104945454A - Preparation method of pure micronized diosmin - Google Patents
Preparation method of pure micronized diosmin Download PDFInfo
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- CN104945454A CN104945454A CN201510064589.6A CN201510064589A CN104945454A CN 104945454 A CN104945454 A CN 104945454A CN 201510064589 A CN201510064589 A CN 201510064589A CN 104945454 A CN104945454 A CN 104945454A
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Abstract
The invention relates to a preparation method of pure micronized diosmin, which comprises the following steps: 1) hesperidin phenolic hydroxyl group protection; 2) halogenating reaction; 3) protecting group removal and double bond generation; and 4) drying to obtain the micropowder. The six secondary hydroxyl groups on the hesperidin glycosyl group have low activity, the two hydroxyl groups on 6- and 7'- sites of the flavone parent nucleus are subjected to hydroxyl group protection, the flavone parent nucleus is halogenated to generate halogenated diosmin, and the protecting group removal is performed to obtain the diosmin.
Description
Technical field
The present invention relates to a kind of pure micronize diosmin preparation method.
Background technology
Diosmin (Diosmin), chemical formula: C
28h
32o
15, molecular weight: 608.6, chemical name: 7 [[6-oxygen-(6-deoxidation-α-L-mannopyranose base)-β-D-glucopyranose-] oxygen]-5-hydroxyl-2-(3-hydroxy-4-methoxyphenyl)-4 hydrogen-benzopyran-4-one.CAS No.520-27-4, flavonoid compound, English another name: 7-[[6-O-(6-Deoxy-α-L-mannopyranosyl)-β-Dglucopyranosyl] oxy]-5-hydroxy-2-(3-hy droxy-4-methoxyphcnyl)-4H-1-benzopyran-4-one.Have another name called foreign first Sui glycosides, diosmin, cloth tangerine glycosides, pale yellow crystals sample powder, water-soluble hardly, be dissolved in dimethyl sulfoxide (DMSO), be dissolved in ethanol hardly, be dissolved in rare basic solution.Structural formula is as follows:
Diosmin (Diosmin) has another name called foreign first Sui glucoside, diosmin, cloth tangerine glucoside, molecular formula C
28h
32o
15molecular weight 601, be present in the root of rutaceae Shinyleaf Pricklyash Root Zanthoxylum nitidum (RoxbDC.) and the fruit of Buddha's hand Citrus modicaL.Var.Sarcodactylis (Noot.) Swinglo, extract in lemon CitruslimonBurm. pericarp.For 7-position is connected with the flavonoid medicine of disaccharide base, the earliest nineteen twenty-five by Scrophularia nodosa in extraction and isolation obtain, or it is semi-synthetic obtained through Hesperidin, for 7-position is connected with the flavonoid medicine of disaccharide base, drug use is used as in 1969, developed by French Shi Weiya company, in listing in 1987, trade(brand)name Alvenor.Diosmin is the various hemorrhoid of a kind for the treatment of newly and chronic venous insufficiency, pure, micronized flavonoid compound.In Europe, diosmin as the use of vascular protection medicament and chronic venous disease therapeutical agent more than 30 years.There is following pharmacological action: 1) strengthen intravenous tension and cause the contraction of vein stronger than other drugs such as rutins, diosmin has special affinity for vein and do not affect Arterial system, treatment hemorrhoid, chronic venous insufficiency etc.; 2) improve that microcirculation diosmin significantly can reduce the sticking of white corpuscle and vascular endothelial cell, divides a word with a hyphen at the end of a line, disintegration, release Inflammatory substances, thus reduce the permeability of capillary vessel and strengthen its tension force, its effect comparatively rutin, Hesperidin is eager to excel, reduce blood viscosity, strengthen red blood cell velocity and reduce microcirculation stasis, be used for the treatment of again hypertension and arteriosclerotic assisting therapy; 3) promote that lymphatic return diosmin increases lymphatic drainage speed and contraction, thus accelerate the backflow of interstitial fluid, improve lymphatic return, alleviate oedema.In recent years, some new effects of diosmin are more and more subject to people's attention, researchist find, its antitumor, treatment diabetes, anti-inflammatory etc. in show good activity.In recent years, diosmin is applied more and more clinically, achieves good clinical effectiveness.Impurity structural formula in diosmin is as follows:
Take a broad view of domestic and foreign literature, Hesperidin dehydrogenation mode roughly has three kinds: bromine dehydrogenation; Iodine dehydrogenation; The dehydrogenation of NBS/ peroxidation toluoyl.Bromine has dehydrogenation to react in two steps to orange peel, and technique is loaded down with trivial details, complicated condition, and will use toxic reagent bromine water, and cost is high, and the traditional technology generally adopted take Hesperidin as raw material, product yield 56%, content 90%.The principal feature of traditional technology is that Technology is very complicated, the production cycle is long, yield is low, cost is high.The purity of its raw material in the synthesis technique of diosmin--Hesperidin abstraction and purification is the key factor ensureing synthesis diosmin content yield, and controlling reasonable operation condition, is the principal element affecting diosmin quality and yield.Horowitz Robert M.GeatiLi Rruno is at " Flavonoid Compound of Cilous.Isolation and Structure of erioditcyol Glycoside " (JAM chem.Soc, 1960, 82 (11): 2803) in bromine to Hesperidin dehydrogenation, react in two steps, technique is loaded down with trivial details, complicated condition, and use toxic reagent bromine water, cost is very high, yield only has 56.2%, content is 92.0%, with NBS/ benzoyl peroxide to Hesperidin dehydrogenation, complex process, need special reagent, cost is higher, yield is low, all be not suitable for suitability for industrialized production, rule thought by chapter, Zhang Wei in " fine chemistry chemical and intermediate handbook " (Beijing: Chemical Industry Press, 2004:705) with iodine to Hesperidin dehydrogenation, take pyridine as solvent, technological process is comparatively simple, and yield reaches 94%, but content is not quite clear, Yang Ailing is in " extraction processes of Hesperidin and series product thereof " (fine chemistry industry, 2002,19 (5): 259-261) in, the way yield of report only reaches 56%, and will use aceticanhydride, pyridine, bromine gas, methylene dichloride etc., reagent is more, operational difficulty, Feng Xuan, Zhu Xing piece, Li Xiaoye is at " diosmin improvement in synthesis " (Journal of the Fourth Military Medical University, 2008,29 (21): 1947) though the synthesis technique of middle report Hesperidin is without the pyridine strong alkaline substance such as sodium hydroxide and salt of wormwood, serious to equipment corrosion, and yield is only 70%, content is not quite clear, Dan Yang, Li Gaoyang, Wang Qiuan etc. adopt iodine/pyridine dehydrogenation in " the semi-synthetic 5 kinds of biological activity flavonoid compounds of Hesperidin " (organic chemistry, 2008,28 (6): 1024-1028), and yield is higher, but content is not quite clear, Luo Meng have employed bromine and iodine two kinds of mode dehydrogenations, iodine dehydrogenation yield 69%, content 99% in " the synthesis of Ao Si meter and research " (chemical intermediate, 2004,6:29-30), bromine dehydrogenation yield only 58%, content 89%.
Diosmin was through the development of nearly 30 years, and by treatment varix originally, lower abdomen is little swollen, improves intravenous tension, regulates microcirculation, develops into now clinically for hemorrhoid and limbs venous return obstacle.Current micronization diosmin can obviously alleviate patient with operation lower limb pain, and swelling is disappeared.Quality product reaches European Pharmacopoeia standard (EP8.3) and China national standards of pharmacopoeia completely, and quality product is very stable.Natural resources is day by day deficient, by improving original technique, science, rationally, comprehensively, efficiently utilizes existing resource, or adopts new technology, develops new resource, can make enterprise's save energy, reduce material consumption energy consumption, reduce product cost.
The present invention utilizes on Hesperidin glycosyl 6 secondary hydroxyls, and activity is not strong, flavones parent nucleus has upper two hydroxyls in 6-position and 7 '-position, through phenolic hydroxyl group protection, then halo flavones parent nucleus, obtain diosmin through steps such as Deprotections.
Summary of the invention
The present invention aims to provide a kind of pure micronize diosmin preparation method.
Technical solution of the present invention is:
A kind of pure micronize diosmin preparation method, comprises the steps:
(1) trimethyl orthoacetate or triethly orthoacetate method is adopted, Hesperidin is with N, dissolve one of in dinethylformamide, pyridine, dimethyl sulfoxide (DMSO), morpholine and methylmorpholine, take tosic acid as catalyzer, stirring reaction 1-3h at 20-30 DEG C, then decompression and solvent recovery, obtains Hesperidin-acetic ester.
(2) burning tin method protection method is adopted; Hesperidin is with N; dissolve one of in dinethylformamide, pyridine, dimethyl sulfoxide (DMSO), morpholine and methylmorpholine; add Dibutyltin oxide, be warming up to 80-100 DEG C of back flow reaction 2-5h, be cooled to less than 10 DEG C; drip diacetyl oxide; at 10 DEG C after insulation reaction 1-3h, rise to 20-30 DEG C of reaction 1-2h, obtain the reaction solution of Hesperidin-acetic ester.
(3) adopt diacetyl oxide method, Hesperidin, to dissolve one of in DMF, pyridine, dimethyl sulfoxide (DMSO), morpholine and methylmorpholine, adds in diacetyl oxide, then adds potassium acetate, is heated to 115 DEG C and constant temperature 3 hours.Add ethanol after cooling, the reaction solution of Hesperidin-acetic ester can be obtained.
One of (4) halide reagent is bromine, sodium iodide, potassiumiodide, trityl chloride, in sulfur oxychloride
(5) crude product is dissolved in the sodium hydroxide solution of 5-20%, and 20-30 DEG C of reaction 1h, decolour at adding 5-10% (W/V) gac 20-30 DEG C 30min, adjustment of acidity, precipitation, and washing, obtains diosmin.
(6) select high velocity air to pulverize in, material size 3mm, product granularity 2-5 μm, air pressure 0.7-85Mpa, particle shape is good, narrow particle size distribution, measures granularity with BT-9300H laser particle analyzer.
Embodiment
Mode one: load onto mechanical stirrer, condenser, thermometer in 250mL there-necked flask, then adds Hesperidin 50g, DMF 250mL, and suitable intensification is stirred to Hesperidin and all dissolves.Add sherwood oil 50mL and Dibutyltin oxide 25g again, be warming up to 90 DEG C of back flow reaction 2-5h, be cooled to less than 10 DEG C, drip the DMF 30mL containing 10mL diacetyl oxide.At 10 DEG C, after insulation reaction 1-3h, 20-30 DEG C of reaction 1-2h is risen to after dropwising.After reaction terminates, add the mixing of a small amount of water, with 100,80,60mL petroleum ether extraction three times, reservation lower floor liquid, for reaction product, the underpressure distillation of sherwood oil liquid, overhead product is sherwood oil, and the liquid after concentrated is dripped 95mL 20%NaOH solution, generate white precipitate Dibutyltin oxide, filter, with distilled water wash, vacuum-drying.Lower floor's reaction solution is heated to 95 DEG C of azeotropic dehydrations, purifies the remaining liq after moisture at vacuum tightness-(0.090-0.094) Mpa, and concentrated at temperature 70-80 DEG C, cooling, obtains the concentrated solution of Hesperidin-acetic ester.Add the mixing of 60mL ethyl acetate after being dissolved by Hesperidin-acetic ester 300mL DMF, join in 500mL there-necked flask, add 2.5 sodium iodides, be slowly warming up to 80 DEG C of backflow 3h, then be warming up to 100 DEG C of backflow 4h.Reaction terminates rear cooling, add 400,300,200mL extraction into ethyl acetate 3 times, combined ethyl acetate.Acetic acid ethyl fluid is with after isopyknic water washing 2-3 time, add 5-10% (W/V) gac to decolour at 80 DEG C 30min, at vacuum tightness-(0.025-0.046) Mpa, concentrated at temperature 40-60 DEG C, leave standstill cooling, crystal is used a small amount of petroleum ether, obtain iodo Hesperidin-acetic ester, getting iodo Hesperidin-acetic ester crude product after drying is dissolved in the sodium hydroxide solution of 5-20%, 20-30 DEG C of reaction 1h, and decolour at adding 5-10% (W/V) gac 20-30 DEG C 30min, adjustment of acidity, precipitation, washing, obtains diosmin.Select high velocity air to pulverize, material size 3mm, product granularity 2-5 μm, air pressure 0.7-85Mpa, particle shape is good, narrow particle size distribution, measures granularity with B T-9300H laser particle analyzer.
Hesperidin 80g, normal hexane 60mL is added, DMF 400mL, back flow reaction 4-6h at Dibutyltin oxide 46g, 80-100 DEG C in mode two: 500mL there-necked flask.Reaction solution is cooled to less than 5 DEG C, drips diacetyl oxide 8.5g, isothermal reaction 2h at 20 DEG C.Stratification, divides normal hexane phase with separating funnel, then use 120,100,80mL n-hexane extraction 3 times.Collect lower floor's liquid, obtain the DMF solution of Hesperidin-acetic ester.At vacuum tightness-(0.090-0.094) Mpa, concentrated at temperature 70-80 DEG C, cooling, vacuum-drying, obtains Hesperidin-acetic ester crude product, and Hesperidin-acetic ester crude product is with N, dinethylformamide solution 300mL dissolves, add ethyl acetate 120mL again, add sulfur oxychloride, be warming up to 70-80 DEG C, backflow 1-3h, be cooled to 20 DEG C, after having reacted, add liquid caustic soda neutralization.Reaction solution with 400,300, the extraction of 200mL toluene, combining extraction liquid, adds 5-10% (W/V) activated carbon decolorizing 30min.Condensing crystal, obtains chloro Hesperidin-acetic ester product.Chloro Hesperidin-acetic ester 40g is dissolved in 80mL methyl alcohol, getting chloro Hesperidin-acetic ester crude product after drying is dissolved in the sodium hydroxide solution of 5-20%, 20-30 DEG C of reaction 1h, decolour at adding 5-10% (W/V) gac 20-30 DEG C 30min, adjustment of acidity, precipitation, washing, obtains diosmin.Select high velocity air to pulverize, material size 3mm, product granularity 2-5 μm, air pressure 0.7-85Mpa, particle shape is good, narrow particle size distribution, measures granularity with BT-9300H laser particle analyzer.
30g Hesperidin, Dibutyltin oxide 65g, N is added in mode three: 250mL there-necked flask, dinethylformamide 160mL and sherwood oil 60mL mixes, load onto prolong and temperature takes into account agitator, be heated to 80-90 DEG C of back flow reaction 3-6h, after reaction terminates, be cooled to 15 DEG C, drip diacetyl oxide 36g, control temperature is no more than at 20 DEG C, dropwises, and reacts 3h at 15-20 DEG C.Reaction terminates, with 60,50,40mL petroleum ether extraction three times, the underpressure distillation of DMF phase, obtains faint yellow glutinous thick liquid Hesperidin-acetic ester after evaporate to dryness.By obtained Hesperidin-acetate syrup 30g 200mL N, dinethylformamide dissolves, be transferred in 500mL there-necked flask, add 120mL ethyl acetate, drip sulfur oxychloride lentamente, control to drip sulfur oxychloride speed, temperature is made to remain on less than 10 DEG C, dropwise stirring reaction 3h at 70-80 DEG C of temperature, chloro terminates rear reaction solution and is cooled to room temperature, underpressure distillation obtains soup compound, be dissolved in the sodium hydroxide solution of 5-20%, 20-30 DEG C of reaction 1h, decolour at adding 5-10% (W/V) gac 20-30 DEG C 30min, adjustment of acidity, precipitation, washing, obtain diosmin.Select high velocity air to pulverize, material size 3mm, product granularity 2-5 μm, air pressure 0.7-85Mpa, particle shape is good, narrow particle size distribution, measures granularity with B T-9300H laser particle analyzer.
In mode four: 500mL mouth bottle, Hesperidin 80g and pyridine 350mL fully dissolves, and adds Dibutyltin oxide 62g, hexanaphthene 80mL, is heated to 80-90 DEG C of backflow 2-5h, cools to 10-20 DEG C, drip the pyridine 60mL containing 30mL acetic anhydride.React 1-3h at control temperature 20 DEG C, with 500,400,300mL hexanaphthene extracts three times, hexanaphthene and Dibutyltin oxide recycle and reuse.Add 450mL toluene in subnatant, treat the next step.Be evaporated to dry by the pyridine solution of Hesperidin-acetic ester, with pyridinium dissolution, add 300mL toluene solution, drip 65mL phosphorus oxychloride, react 1h at temperature control 20 DEG C, then be warming up to 95-105 DEG C of backflow 4h, reaction terminates, and obtains chloro Hesperidin-acetic ester crude product.Chloro Hesperidin-acetic ester crude product is dissolved in the sodium hydroxide solution of 5-20%, and 20-30 DEG C of reaction 1h, decolour at adding 5-10% (W/V) gac 20-30 DEG C 30min, adjustment of acidity, precipitation, and washing, obtains diosmin.Select high velocity air to pulverize, material size 3mm, product granularity 2-5 μm, air pressure 0.7-85Mpa, particle shape is good, narrow particle size distribution, measures granularity with BT-9300H laser particle analyzer.
Mode five: Hesperidin 75g add 100mL dewater after dimethyl sulfoxide (DMSO) in, stir at 20-30 DEG C, slowly drip 10g trimethyl orthoacetate, and add 150mg tosic acid, stirring reaction 1-3h at 20-30 DEG C, concentrating under reduced pressure reactant, reclaim under reduced pressure dimethyl sulfoxide (DMSO), obtain syrup, add ethyl acetate and methyl alcohol, heated and stirred 1h, cooling, separating out yellowish pulverulent solids, is Hesperidin-acetic ester.Getting Hesperidin-acetic ester 10g is dissolved in dimethyl sulfoxide (DMSO) in solution, and under 5-10 DEG C of condition, slowly drip the sulfur oxychloride solution 73mL containing 23 g bromine waters, 75-85 DEG C of insulation reaction 3-4h, concentrating under reduced pressure, obtains bromo Hesperidin-acetic ester.Bromo Hesperidin-acetic ester crude product is obtained through recrystallization.Get bromo Hesperidin-acetic ester crude product broad in the sodium hydroxide solution of 5-20%, 20-30 DEG C of reaction 1h, decolour at adding 5-10% (W/V) gac 20-30 DEG C 30min, adjustment of acidity, precipitation, and washing, obtains diosmin.Select high velocity air to pulverize, material size 3mm, product granularity 2-5 μm, air pressure 0.7-85Mpa, particle shape is good, narrow particle size distribution, and with BT-9300H, laser particle analyzer measures granularity.
Add Hesperidin 50g in mode six: 500mL there-necked flask, morpholine 200mL, triethly orthoacetate 25g, tosic acid 1.5g, 20-25 DEG C of reaction 3-5h, is evaporated to dry syrupy shape Hesperidin-acetic ester.Add anhydrous morpholine and dissolve Hesperidin-acetic ester, potassiumiodide dissolves with DMF, and after dripping, 80-90 DEG C of reaction 4-5h, removal of solvent under reduced pressure, obtains syrup.Iodo Hesperidin-acetic ester crude product is dissolved in the sodium hydroxide solution of 5-20%, and 20-30 DEG C of reaction 1h, decolour at adding 5-10% (W/V) gac 20-30 DEG C 30min, adjustment of acidity, precipitation, and washing, obtains diosmin.Select high velocity air to pulverize, material size 3mm, product granularity 2-5 μm, air pressure 0.7-85Mpa, particle shape is good, narrow particle size distribution, measures granularity with BT-9300H laser particle analyzer.
Mode seven: 50g Hesperidin is added in 200mL dimethyl sulfoxide (DMSO), 30mL triethly orthoacetate and 0.30g tosic acid is added under stirring in 20 DEG C, stirring reaction 2.5h, then reclaim under reduced pressure dimethyl sulfoxide (DMSO), Hesperidin-acetic ester 40g is added in 200mL pyridine, be cooled to less than 20 DEG C and drip 50mL sulfur oxychloride, be heated to 92 DEG C of back flow reaction 1.5h, obtain chloro Hesperidin-acetic ester.Get in the 150mL methyl alcohol that 30g chloro Hesperidin-acetic ester is dissolved in containing 1.5g sodium methylate, in stirring at room temperature reaction 1.5h, add 2g activated carbon decolorizing, stir 15min, filter decompressing and extracting and obtain product diosmin.Select high velocity air to pulverize, material size 3mm, product granularity 2-5 μm, air pressure 0.7-85Mpa, particle shape is good, narrow particle size distribution, measures granularity with BT-9300H laser particle analyzer.
Mode eight: 50g Hesperidin and 60mL methylmorpholine are dissolved in 100mLN, in dinethylformamide, divide after 30min and add 150.0g trityl chloride altogether three times, continue heating 3.5h, be dissolved into after solution being vacuumized drying in diacetyl oxide, add 15g potassium acetate again, be heated to 115 DEG C and constant temperature 3 hours, Hesperidin-acetate solution.Hesperidin-acetic ester is dissolved in 800ml toluene, and be cooled to 0 DEG C, passing into hydrogen chloride gas has throw out to generate, cross filter cake thing toluene to clean, become particulate state, at room temperature add thionyl chloride 50mL, by this solution at 80-90 DEG C of reaction 2.5h, be cooled to 40 DEG C, add 200mL again and be water-cooled to 0 DEG C, filter after being uniformly mixed liquid, obtain crude product chloro Hesperidin-acetic ester, it is dissolved in 200mL hot methanol, 1.5h is stirred under vacuum condition, add potassium hydroxide and regulate pH9-10, again stir this solution of neutralization, filter, filtrate is concentrated after 2g gac and the decolouring of 2g diatomite, add 100mL ethyl acetate, namely diosmin is separated out.Select high velocity air to pulverize, material size 3mm, product granularity 2-5 μm, air pressure 0.7-85Mpa, particle shape is good, narrow particle size distribution, measures granularity with BT-9300H laser particle analyzer.
80g Hesperidin and pyridine 350mL is added in mode nine: 1000mL there-necked flask, be heated to 60 DEG C, Hesperidin is all dissolved, be cooled to room temperature, add sherwood oil 200mL and Dibutyltin oxide 72g, be warming up to 80-90 DEG C of backflow 2-5h, then cool to 10-20 DEG C, drip the pyridine solution 100mL being dissolved with 30mL acetic anhydride.Control temperature 10-15 DEG C, reacts 1h under this temperature.Then 30 DEG C of reaction 1.5h are warming up to.By reaction solution impouring 1000mL separating funnel, with 500,400,300mL sherwood oil divides and extracts organotins 3 times.By Hesperidin-ethyl ester pyridine solution decompressing and extracting solvent, add a small amount of ethanol, obtain white needle-like crystals.Hexanaphthene and Dibutyltin oxide recycle and reuse.Add the pyridine solution of 300mL Hesperidin-acetic ester in there-necked flask, toluene solution drips 40mL phosphorus oxychloride at 0-5 DEG C, at dropping temperature is no more than 10 DEG C, at 10 DEG C, react 1h.In reactor, add 1.5g S-WAT, be warming up to 70-80 DEG C of reaction 1h, then be warming up to 90-100 DEG C of back flow reaction 4h.Cooling, reduced under vacuum obtains enriched material, and obtain chloro Hesperidin-ethyl ester crystal, mother liquor recrystallization reclaims further.Getting chloro Hesperidin-acetic ester crude product is dissolved in the sodium hydroxide solution of 5-20%, and 20-30 DEG C of reaction 1h, decolour at adding 5-10% (W/V) gac 20-30 DEG C 30min, adjustment of acidity, precipitation, and washing, obtains diosmin.Select high velocity air to pulverize, material size 3mm, product granularity 2-5 μm, air pressure 0.7-85Mpa, particle shape is good, narrow particle size distribution, measures granularity with BT-9300H laser particle analyzer.
Claims (7)
1. a pure micronize diosmin preparation method, is characterized in that, be raw material with Hesperidin, the method includes the steps of:
(1) protection of Hesperidin phenolic hydroxyl group.
(2) halogenating reaction.
(3) Deprotection and double bond generate.
(4) dry, micro mist.
2. a kind of pure micronize diosmin preparation method as claimed in claim 1; it is characterized in that; trimethyl orthoacetate or triethly orthoacetate method is adopted in step (1); Hesperidin is with N; dissolving one of in dinethylformamide, pyridine, dimethyl sulfoxide (DMSO), morpholine and methylmorpholine, take tosic acid as catalyzer, stirring reaction 1-3h at 20-30 DEG C; then decompression and solvent recovery, obtains Hesperidin-acetic ester.
3. a kind of pure micronize diosmin preparation method as claimed in claim 1; it is characterized in that; burning tin method protection method is adopted in (1) in step (1); Hesperidin is with N; dissolve one of in dinethylformamide, pyridine, dimethyl sulfoxide (DMSO), morpholine and methylmorpholine; add Dibutyltin oxide; be warming up to 80-100 DEG C of back flow reaction 2-5h; be cooled to less than 10 DEG C; drip diacetyl oxide; at 10 DEG C after insulation reaction 1-3h, rise to 20-30 DEG C of reaction 1-2h, obtain the reaction solution of Hesperidin-acetic ester.
4. a kind of pure micronize diosmin preparation method as claimed in claim 1; it is characterized in that; diacetyl oxide method is adopted in step (1); Hesperidin is with N; dissolve one of in dinethylformamide, pyridine, dimethyl sulfoxide (DMSO), morpholine and methylmorpholine; add in diacetyl oxide, then add potassium acetate, be heated to 115 DEG C and constant temperature 3 hours.Add ethanol after cooling, the reaction solution of Hesperidin-acetic ester can be obtained.
One of 5. a kind of pure micronize diosmin preparation method as claimed in claim 1, is characterized in that, in step (2), halide reagent is bromine, sodium iodide, potassiumiodide, trityl chloride, in sulfur oxychloride.3-4h is reacted at 70-110 DEG C.
6. a kind of pure micronize diosmin preparation method as claimed in claim 1; it is characterized in that; in step (3), crude product is dissolved in the sodium hydroxide solution of 5-20%; 20-30 DEG C of reaction 1h; decolour at adding 5-10% (W/V) gac 20-30 DEG C 30min, adjustment of acidity, precipitation; washing, obtains diosmin.
7. a kind of pure micronize diosmin preparation method as claimed in claim 1; it is characterized in that; step selects high velocity air to pulverize in (4); material size 3mm; product granularity 2-5 μm, air pressure 0.7-85Mpa, particle shape is good; narrow particle size distribution, measures granularity with BT-9300H laser particle analyzer.
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| CN106478750A (en) * | 2016-08-30 | 2017-03-08 | 成都欧康医药股份有限公司 | A kind of preparation method of diosmin |
| CN108003192A (en) * | 2016-11-01 | 2018-05-08 | 潘嘉慧 | The structure and its synthetic method of flavone compound |
| CN111100104A (en) * | 2019-12-26 | 2020-05-05 | 陕西嘉禾药业有限公司 | Preparation method of diosmetin |
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