CN102653549A - Synthesis method of diosmin raw medicine meeting EP7 version quality standards - Google Patents
Synthesis method of diosmin raw medicine meeting EP7 version quality standards Download PDFInfo
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- CN102653549A CN102653549A CN201110447091XA CN201110447091A CN102653549A CN 102653549 A CN102653549 A CN 102653549A CN 201110447091X A CN201110447091X A CN 201110447091XA CN 201110447091 A CN201110447091 A CN 201110447091A CN 102653549 A CN102653549 A CN 102653549A
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Abstract
The invention discloses a synthesis method of diosmin. A microwave-assisted heating method is adopted, I2 and NaI are used as catalysts, the ethanol solution of K2CO3 and NaOH and a pyridine mixed solvent are used as reaction solvents for establishing a reaction system, hesperidin is dehydrogenized to prepare diosmin in one step, and the dehydrogenation process avoids high temperature and avoids use of a large amount of high-boiling-point toxic solvents such as pyridine, dimethyl sulfoxide and the like in the reaction solvent system. Through the invention, the total synthesis yield of the diosmin is more than 80%, and the product quality meets the EP7.0 standards. The method disclosed by the invention has the technical characteristics of easiness in acquisition of raw materials, mild reaction conditions, short reaction time, simplicity and convenience in operation, low production cost, good product quality and the like, and is suitable for industrialized production.
Description
Technical field
[0001] biological medicine, chemosynthesis.
Background technology
Diosmin: another name 7-rutinoside, diosmin, English name Diosmin, chemical name 3', 5,7-trihydroxy--4'-methoxy flavone, molecular formula C
28H
32O
15, molecular weight 608.54, CAS number: 520-27-4, EINECS number: 208-289-7.Pearl or faint yellow microcrystal powder, water-soluble hardly, be dissolved in DMSO 99.8MIN., be dissolved in ethanol hardly, be dissolved in rare basic soln.
One, has the effect of vitamin P appearance, can reduce vascular fragility and unusual permeability, be used to prevent and treat hypertension and arteriosclerotic assisting therapy again, be used to treat the crisp effect of capillary vessel and be eager to excel, and have the low characteristics of toxicity than rutin, Hesperidin.
Two, patient's lower limb pain degree change and the swelling degree change basically identical that disappears behind the bone surgery, micronize diosmin group compare with control group swelling and pain relief obviously in advance and alleviation speed also obviously accelerate.(Chinese the 9th volume 22 phases of younger brother of clinical rehabilitation, 2005-06-14 publishes)
Three, diosmin has good and clinical curative effect and security to slight internal piles.(the healthy digest in China and foreign countries the 8th volume the 16th phase World Health Digest Medical Periodiead April in 2011)
Four, diosmin associating MAYINGLONG MUSK HEMORRHOID UNGUENTUM application of treatment thrombosed hemorrhoids is evident in efficacy, is superior to independent medication.(medical Leader the 29th the 7th phase of volume of July in 2010)
Five, the hip bath of diosmin associating credit for hard work soup is a treatment inflammatory mixed hemorrhoids method preferably.(2011 the 51st volumes of Shandong medicine o. 11th)
The present situation of diosmin: diosmin industry statistic; Global annual consumption mainly concentrates on Europe, South America about 4000t, also there is certain demand in Africa, Asia; Because the advantage of diosmin; Make a lot of countries slowly replace similar medicine with diosmin, demand has good prospects in continuous growth.Hesperidine is a main raw material of producing diosmin, and China is the major country of production of hesperidine, and YO is more than 6000t, and therefore producing diosmin has inborn advantage.But because the backwardness of technology; China diosmin manufacturer seldom; At present the general production technique that adopts of each manufacturer is two kinds of bromine water oxidizing reaction and iodine substitution reactions; But because of the water insoluble and most organic solvents of diosmin (like methyl alcohol, ethanol, the solvent that acetone, benzene etc. are commonly used), temperature of reaction is high, long reaction time.As people's such as the Zhang Guangyue of the medicine company of pulling together, Zhang Qiang patent CN200610021185.X adopts high boiling point DMF to do action solvent exactly, and anti-temperature of reaction is more than 120 ℃, and reaction times 8-12 hour, it is difficult that its shortcoming is that high boiling organic solvent reclaims, and dissolvent residual is high in the product.Temperature of reaction is high, long reaction time, and energy consumption is big, and cost is high.Document " Luo Meng. synthetic and research [J] chemical intermediate, 2004, the 6:29-30. of ground Ao Shimi " report that mostly the bright preparation of Christian Dior is that Hesperidin takes off hydroformylation step through iodine and makes, this method is solvent with the pyridine, as is amplified to industriallization with serious environment pollution.The Fourth Military Medical University's journal (" the true Feng Xuan of the improvement of the bright synthesis technique of Christian Dior, the Zhu Xingmei of 2008,29-(21) reports of J Fourth Mil Med-Univ); Li Xiaoye " utilize diosmin to be dissolved in the physical features of diluted alkaline; Use adds the alcohol solvent of alkali and does action solvent, has solved the dissolvent residual problem, but temperature of reaction is more than 150 ℃; Conventional heating means are difficult to control in the production, need high-temperature high-pressure apparatus.Operation easier is big, and energy consumption cost is also high.In a word, according to the market survey analysis, the energy consumption of present Chinese diosmin industry is big, environmental pollution is serious, yield is low, dissolvent residual is difficult to resolve and determines, capacity for technological innovation is weak.In order to make good use of the resources advantage of China, solve the difficulty that present industry runs into, the technology that through in many ways research, the experiment of production repeatedly, obtain that a cover greatly reduces cost, yield is high, is beneficial to environmental protection.
Summary of the invention
The objective of the invention is to overcome the deficiency of above-mentioned technological method, provide a kind of and greatly reduce production costs, the enabling environment protection, reduce the product dissolvent residual, improve the quality of products, make it to reach the working method of the diosmin that meets EP7 version pharmacopeia specification of quality.
Characteristic of the present invention is to utilize the microwave-assisted heating technique, uses alkaline ethanol and pyridine mixed solvent as action solvent, makees catalyzer with iodine, makes Hesperidin take off hydroformylation step through iodine at a lower temperature and makes and use diosmin.Microwave assisting method has the reaction conditions gentleness, reaction fast, reaction times weak point, few, the energy-efficient consumption reduction of solvent usage quantity, less contamination, characteristics such as quality product height.
The present invention realized through following several steps:
The first step main reaction: 1 part of hesperidine raw material is added 0.5 part of K
2CO
3, 0.1 part of NaOH, 0.3 part of iodine (mass ratio) drop into reaction kettle successively, adds the ethanolic soln of 5 times of amounts 90%, the pyridine solvent of 1 times of amount stirs; With microwave heating to 110 ± 5 ℃, stop microwave heating, add the pyridine solvent of 2 times of amounts again to still, the Soiodin of 0.1 times of amount; Change insulation when being steam heated to 110 ± 5 ℃, stirring reaction 3-4 hour, sampling; Detect with the HPLC detection method, when the hesperidine peak area less than the diosmin peak area 5% the time termination reaction, the heating recovery solvent.
The second step press filtration: the paste that has reclaimed behind the organic solvent adds 2 times of amount methyl alcohol, carries out press filtration, the recovery iodine liquid that gives up; After recovery finishes, clean, clean till the water outlet water white transparency with 60 ± 5 ℃ purified water; Press dry; Unload filter cake, get the diosmin bullion, yield about 150% (weight in wet base).
The 3rd step purifying: the sodium hydroxide solution of the 2%-5% of 3-4 times of bullion weight is dropped in the dissolving vessel, drop into the bullion stirring and dissolving, add 5-8 again and doubly measure pure water and stir; Be filled in the crystallization kettle with stainless steel sheet frame strainer; Transfer PH to 6.5-7.5 with industrial concentrated hydrochloric acid, add small amount of methanol again, behind the stirring 20-40min; Staticly settle 0.7-1.3 hour.
The 4th step washing: the material in the crystallizer is squeezed in the pressure filter, cleaned, clean till the water outlet water white transparency, unload filter cake after pressing dry with 60 ± 5 ℃ purified water, must the diosmin elaboration, about 115% (weight in wet base, the water cut about 30%) of yield
The 5th step drying, pulverizing, mixing: work in-process are dropped into baking oven; Under 80 ± 5 ℃ of conditions of temperature the dry 5-8 of dry vacuum hour, dried material is pulverized with Universalpulverizer, drop into bipyramid then and always mix machine and mix; Rotating speed 10-18r/min; The positive and negative 15-35min that respectively overturns must meet the diosmin finished product of EP7 version specification of quality, and product yield can reach more than 85%.
Description of drawings
AttachFig. 1: the technical process of refining iodine
Accompanying drawing 2: diosmin synthesis route figure
Embodiment
Main reaction: with the 80Kg hesperidine, 40Kg soda ash, the ethanol of 400kg90%, 80L pyridine, 24kg iodine drop into reaction kettle successively, have sealed the still mouth, stir, and with microwave heating to 110 ℃, insulated and stirred is until hesperidine all dissolves about ten minutes.After the hesperidine dissolving fully, slowly add the 80L pyridine solvent, add Soiodin 8Kg again; Be heated to 110 ℃, insulated and stirred reaction 3-4 hour, sampling then; Detect with the HPLC detection method, when the hesperidine peak area less than the diosmin peak area 5% the time termination reaction, heating recovery solvent pyridine.
Press filtration: the paste that has reclaimed pyridine adds 25Kg methyl alcohol, carries out press filtration, reclaims useless iodine liquid, reclaim finish after, clean with 62 ℃ purified water, clean till the water outlet water white transparency, 3 tons of waters unload filter cake, get the diosmin bullion, 125.4Kg.
Purifying: 16Kg sodium hydroxide is dropped in the dissolving vessel, add purified water 500Kg, stirring and dissolving; Then bullion is dropped in the dissolving vessel, add 1 ton of pure water again and stir, be filled in the crystallization kettle with stainless steel sheet frame strainer; Add 42Kg hydrochloric acid, transfer PH to 6.7, add 25Kg methyl alcohol again; After stirring 30min, staticly settle 1 hour.
Washing: the material in the crystallizer is squeezed in the pressure filter, cleaned with 61 ℃ purified water, clean till the water outlet water white transparency, 4 tons of waters unload filter cake, must the diosmin elaboration, and 118.5Kg.
Drying, pulverizing, mixing: work in-process are dropped into baking oven; Drying is 11.2 hours under 82 ℃ of conditions of temperature, and dried material is pulverized with Universalpulverizer, drops into the always mixed machine of bipyramid then and mixes; Rotating speed 15r/min; The positive and negative 20min that respectively overturns gets diosmin finished product 72Kg, and yield is 90.0%.
Packing: carry out internal packing with double-deck medical polyethylene bag, put into fiber can after the assay was approved, change stockyard over to.
The recovery of iodine: the iodine filtrating that contains that produces in the press filtration operation is slowly added sulfuric acid, regulate PH to 4, placed underpressure distillation 5 hours; Collect high boiling fraction, slowly add ydrogen peroxide 50 20Kg, placed 2 hours; Filter, obtain the iodine that reclaims in the filter cloth, refiningly again again just can obtain making with extra care iodine!
The processing of moisture in the pyridine: the pyridine that contains moisture after the 400Kg recovery is added in the reaction kettle, add Pottasium Hydroxide 35Kg again, be heated to 105 ± 5 ℃; (pyridine that came out before 105 ℃ is preceding liquid to collect pyridine; Belong to unacceptable product, return again in the reaction kettle, what come out after 105 ℃ is salable product); Detect with the karl Fischer moisture content tester, less than 2%.
Claims (6)
1. diosmin compound method that meets EP7.0 version quality standard, of the present invention to the effect that we adopt with I
2, NaI makes catalyzer, with K
2CO
3, NaOH ethanolic soln and pyridine mixed solvent be system as action solvent; Adopt the microwave-assisted heating means; Hesperidin is taken off hydroformylation step, and to prepare Christian Dior department bright, and with total recovery more than 80%, and certain embodiments has avoided high temperature and reaction solvent system to use high boiling point noxious solvents such as pyridine, DMSO 99.8MIN. in a large number. and this method has that raw material is easy to get, reaction conditions gentle, the reaction times is short, easy and simple to handle; Characteristics such as production cost is low are applicable to suitability for industrialized production.
2. diosmin synthetic process according to claim 1 is characterized in that using I
2With the NaI mixture catalyzer, its consumption is that the 0.2--0.8 of raw material doubly measures, and is preferably 0.4 amount; I
2With the ratio of NaI be (1:4)---(4:1). be preferably 3:1.
3. diosmin synthetic process according to claim 1 is characterized in that heating means have adopted the microwave-assisted heating.
4. diosmin synthetic process according to claim 1 is characterized in that the reaction solvent system uses ethanol and pyridine mixed solvent, and its consumption is that the 3--10 of raw material doubly measures, and is preferably the 5-7 amount; The ratio of ethanol and pyridine is (1:5)---(5:1). be preferably 5:2.
5. according to power. profit requires 1 described diosmin synthetic process, it is characterized in that reaction solvent system adding yellow soda ash and sodium hydroxide are to help the dissolving of Hesperidin and diosmin
,K
2CO
3Consumption be the 10%--80% of raw material, be preferably 50%, the consumption of NaOH is the 5%--50% of raw material, is preferably 10%.
6. diosmin synthetic process according to claim 1 is characterized in that temperature of reaction is 90 ℃--150 ℃, being preferably 105 ℃--115 ℃.
7. diosmin synthetic process according to claim 1 is characterized in that the I that uses
2Can carry out recycling with the NaI mixture catalyzer.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875621A (en) * | 2012-10-26 | 2013-01-16 | 成都澜绮制药有限公司 | Synthesis method of diosmin |
| CN103435666A (en) * | 2013-07-30 | 2013-12-11 | 李玉山 | Novel production technology of diosmin |
| CN106967138A (en) * | 2017-04-19 | 2017-07-21 | 成都百特万合医药科技有限公司 | Diosmin production method based on dimethyl sulfoxide system |
| CN107108675A (en) * | 2015-02-03 | 2017-08-29 | 因特奎姆私人控股公司 | The method for preparing diosmin |
| CN108558972A (en) * | 2018-03-28 | 2018-09-21 | 四川青益纯医药科技有限公司 | A kind of preparation method of high-purity diosmin |
| CN114306363A (en) * | 2022-01-05 | 2022-04-12 | 成都亚中生物制药有限责任公司 | Method for industrially preparing citrus flavone bulk drug |
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| CN101089009A (en) * | 2006-06-16 | 2007-12-19 | 四川协力制药有限公司 | Diosmin producing process |
| WO2010092592A2 (en) * | 2009-02-11 | 2010-08-19 | Elder Pharmaceuticals Ltd. | Process for the preparation of diosmin |
| CN102070689A (en) * | 2011-01-25 | 2011-05-25 | 湖南圆通药业有限公司 | Method for producing diosmin |
| CN202011745U (en) * | 2011-01-25 | 2011-10-19 | 湖南圆通药业有限公司 | Waste iodine recycling system for diosmin production |
| CN202010445U (en) * | 2011-01-25 | 2011-10-19 | 湖南圆通药业有限公司 | On-line dehydration system used for main reaction equipment in diosmin production |
-
2011
- 2011-12-28 CN CN201110447091XA patent/CN102653549A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101089009A (en) * | 2006-06-16 | 2007-12-19 | 四川协力制药有限公司 | Diosmin producing process |
| WO2010092592A2 (en) * | 2009-02-11 | 2010-08-19 | Elder Pharmaceuticals Ltd. | Process for the preparation of diosmin |
| WO2010092592A3 (en) * | 2009-02-11 | 2011-09-09 | Elder Pharmaceuticals Ltd. | Process for the preparation of diosmin |
| CN102070689A (en) * | 2011-01-25 | 2011-05-25 | 湖南圆通药业有限公司 | Method for producing diosmin |
| CN202011745U (en) * | 2011-01-25 | 2011-10-19 | 湖南圆通药业有限公司 | Waste iodine recycling system for diosmin production |
| CN202010445U (en) * | 2011-01-25 | 2011-10-19 | 湖南圆通药业有限公司 | On-line dehydration system used for main reaction equipment in diosmin production |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875621A (en) * | 2012-10-26 | 2013-01-16 | 成都澜绮制药有限公司 | Synthesis method of diosmin |
| CN103435666A (en) * | 2013-07-30 | 2013-12-11 | 李玉山 | Novel production technology of diosmin |
| CN103435666B (en) * | 2013-07-30 | 2016-03-16 | 李玉山 | A kind of production new technology of diosmin |
| CN107108675A (en) * | 2015-02-03 | 2017-08-29 | 因特奎姆私人控股公司 | The method for preparing diosmin |
| CN107108675B (en) * | 2015-02-03 | 2020-10-27 | 健康科技生物活性有限个人公司 | Process for preparing diosmin |
| CN106967138A (en) * | 2017-04-19 | 2017-07-21 | 成都百特万合医药科技有限公司 | Diosmin production method based on dimethyl sulfoxide system |
| CN108558972A (en) * | 2018-03-28 | 2018-09-21 | 四川青益纯医药科技有限公司 | A kind of preparation method of high-purity diosmin |
| CN114306363A (en) * | 2022-01-05 | 2022-04-12 | 成都亚中生物制药有限责任公司 | Method for industrially preparing citrus flavone bulk drug |
| CN114306363B (en) * | 2022-01-05 | 2022-11-08 | 成都亚中生物制药有限责任公司 | Method for industrially preparing citrus flavone bulk drug |
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Application publication date: 20120905 |