CN100503627C - Method for preparing high-content troxerutin drug - Google Patents
Method for preparing high-content troxerutin drug Download PDFInfo
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- CN100503627C CN100503627C CNB2006100657184A CN200610065718A CN100503627C CN 100503627 C CN100503627 C CN 100503627C CN B2006100657184 A CNB2006100657184 A CN B2006100657184A CN 200610065718 A CN200610065718 A CN 200610065718A CN 100503627 C CN100503627 C CN 100503627C
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Abstract
The present invention provides a method for synthesizing 3', 4', 7-troxerutin. In the method, rutin and epoxyethane is carried out for hydroxyethylation reaction under the condition that sodium hydroxThe invention offers 3', 4', 7-troxerutin synthetic method. It uses rutin and ethylene oxide to do hydroxyethylation reaction under the catalyzing of sodium hydroxide. Its features are that in the reaide is taken as a catalyst. The method is characterized in that the weight ratio of rutin to water is 1: 1 to 1: 3 in hydroxyethylation reaction, preferably 1: 1 to 1: 1.5; the weight ratio of rutin tction, the weight ratio of rutin and water is 1:1-1:3; optimization is 1:1-1:1.5; the weight ratio of rutin and sodium hydroxide is 100:0.82-100:0.85; adding resin when the pH value of the reaction soo sodium hydroxide is 100: 0.82 to 100: 0.85; the other characteristic of the present invention comprises that when the PH value of reaction liquid is from 9.0 to 9.5, resins are added; the PH value olution is 9.0-9.5 to adjust end point pH value to 9.5-10.3. The method can make high purity and high quality troxerutin. And its 3', 4', 7-troxerutin content is more than 78%; optimization is more thaf the end point of the reaction liquid is adjusted to 9.5 to 10.3 through using resins. The method can prepare a troxerutin product with high purity and high quality. When tested with an HPLC method, n 80%; and the more optimization is more than 85%. the content of 3', 4'7-troxerutin in a crude product of troxerutin which is prepared with the method is more than 78%, preferably more than 80% and more preferably more than 85.
Description
Technical field
The invention belongs to chemical pharmacy field, particularly, the present invention relates to a kind of preparation method of high-content troxerutin drug.
Background technology
The chemical name of troxerutin (Troxerutin) is: 3 ', 4 ', 7-three [O-(2-hydroxyethyl)] rutin, abbreviate 3 ' as, 4 ', 7-Z 6000, it is the water-soluble products that rutin obtains through hydroxyethylation, it has absorptivity and better therapeutic in the better body than rutin, has the capillary permeability of reduction and fragility, improve capillary resistance, suppress platelet aggregation, prevent curative effects such as thrombosis, can be used for treating the hemiplegia due to cerebral thrombosis and the cerebral embolism, aphasia, arteriosclerosis, varix, central retinitis, syndromes before the myocardial infarction, and the vascular permeability diseases such as oedema that raise and cause are especially having good effect aspect the prevention of arterial sclerosis.
CN1056850C discloses a kind of method of synthetic and refining troxerutin (Z 6000), this method is by removing the crystal water on the hydroxyl of C3 ' in the rutin molecule and C4 ' position, avoided the shielding effect of crystal water in building-up process, and by the consumption of alkali in the control reaction and the pH value of accurate controls reaction speed, reaction end and precipitated impurities, make that the content of Z 6000 reaches more than 70% in the product, and remove the impurity in the product more fully.
CN1554353A discloses a kind of active substance 3 ', 4 ', the content of 7-three [O-(2-hydroxyethyl)] rutin is greater than high-content troxerutin drug of 90% and preparation method thereof, it is 1/10～1/3 that this preparation method uses the mol ratio of organic solvent (particular methanol), rutin and the high-efficient homogeneous catalyst (preferred pyridine) of 4-8 times of amounts, in autoclave, feed oxyethane, confined reaction is 2-10 hours under 40-90 ℃ of conditions, add gac, heat filtering, filtrate vacuum are drained and are obtained crude product.
But we discover that rutin belongs to flavonoid compound, and hydrolysis takes place under the higher environment of alkalescence easily.Research report (" percolation process extracts the experimental study of rutin " as Liu Jinyue etc., " Chinese Chinese materia medica science and technology ", 1999 the 6th the 5th phases of volume, 320-321): hydrolysis reaction and oxidizing reaction easily take place in flavonoid rutin compound in the high slightly alkali lye of concentration, the by product of generation is as follows:
The glucoside unit that produces can further be oxidized to phenols and fragrant acids
This two classes by product may further produce hydroxyethylated impurity with reacting ethylene oxide:
Because these impurity do not have the pharmacological action of troxerutin, enter human body and have potential safety hazard.
Therefore, in the ethoxyl etherification of preparation troxerutin, the add-on of control water and sodium hydroxide regulates reaction pH value, and the control reaction end has substantial connection to the purity and the quality of the troxerutin product for preparing.The inventor is through concentrating on studies discovery, in the ethoxyl etherification of preparation troxerutin, by the add-on of control with respect to the water and the sodium hydroxide of rutin material quantity, by in reaction process, adding the pH value that resin comes conditioned reaction, the control reaction end, can prepare high purity and high-quality troxerutin product like this, finish the present invention thus.
Summary of the invention
The object of the present invention is to provide a kind of method for preparing the troxerutin that content is higher, impurity is less.The object of the present invention is achieved like this:
Preparation method of the present invention comprises that rutin and oxyethane are to carry out ethoxyl etherification, heat filtering under the condition of catalyzer, concentrate and drying process at sodium hydroxide, concrete steps are: with rutin in water with the sodium hydroxide salify, then with oxyethane generation ethoxyl etherification.By the consumption of controlling water, sodium hydroxide and the pH value that the adding resin comes controls reaction speed and reaction solution in reaction process, pH value by the control reaction solution is controlled reaction end, and in terminal point adding hydrochloric acid soln conditioned reaction liquid pH value termination reaction, heat filtering, concentrated, vacuum-drying.
Particularly, the troxerutin content that the present invention relates to a kind of one-step synthesis is greater than 78% novel method.This synthetic method is a raw material with rutin, oxyethane, sodium hydroxide is that catalyzer, water are solvent, utilize Zeo-karb in alkaline environment, the ability of absorption heavy metal and transition metal ion has precedence over the character of sodium ion, therefore thereby lowered the concentration of transition metal ion in the aqueous solution, and weakened transition metal ion the katalysis of oxidation side reaction is reached the growing amount that reduces the oxidation by product; Utilize hydrogen type cation exchange resin can be in right amount in alkaline environment in and the tart character of the aqueous solution, thereby reduce troxerutin, rutin or other hydroxyethyl rutins the Quercetin parent nucleus in stronger alkaline environment, the oxidation rate that more definite is in the alkaline environment aqueous solution of pH 〉=9.0 o'clock more precisely is the speed that is oxidized to by product; By control reaction solvent amount and add resin and come controls reaction speed and reaction end accurately, make product in the purified crude product 3 ', 4 ', the content of 7-Z 6000 reaches more than 78%; Can reach more than 92% when adding the nitrogen protection reaction; Weight yield in rutin reaches more than 120%.Alcohols with more definite preferably 1-5 carbon atoms of alcohols; When more first-selected methyl alcohol is made refining solvent, once refiningly can make content reach 95%-99%, the purified molar yield is 80%-90%.This method has easy and simple to handle, and the factory effluent quantity discharged is few, and by-products content is low in the resultant, is of value to the human consumer who takes this product, more preferably is of value to the person in middle and old age human consumer's who takes this product health; Present method has more suitable industrial characteristics.
More particularly, the invention provides a kind of synthetic 3 ', 4 ', the method of 7-Z 6000, this method uses rutin and oxyethane and sodium hydroxide to carry out ethoxyl etherification, it is characterized in that, in ethoxyl etherification, the weight ratio of rutin and water is 1:1～1:3, preferred 1:1～1:1.5; The weight ratio of rutin and sodium hydroxide is 100:0.82～100:0.85.
Another feature of the present invention is when the pH of reaction solution value is 9.0～9.5, adds resin.
Another feature of the present invention is that the pH value of reaction solution terminal point is 9.5～10.3.
Another feature of the present invention is after reaction reaches terminal point, adds aqueous hydrochloric acid and comes termination reaction, and making reaction solution final pH value is 4.0～5.0.
In the troxerutin crude product that method of the present invention prepares 3 ', 4 ', the HPLC mass content of 7-Z 6000 is preferably greater than 80%, more preferably greater than 85% greater than 78%.
The invention has the advantages that:
1. the present invention has reduced the consumption of reaction solvent, has improved reaction density, has shortened the reaction times, has reduced the generation of impurity, has reduced the consumption of oxyethane, thereby has improved product content and reduced cost.
2. the present invention has added resin in the hydroxyethylation stage, and its advantage is:
1. because resin has bigger buffer capacity,, not only make three hydroxyethyls of 3 ', 4 ', 7 obtain sufficient reaction, but also controlled the generation of four hydroxyethyl rutins, improved the yield and the content of product so the pH value raising speed of reaction solution is slower.
2. because resin has stronger adsorptivity, make heavy metal ion in the reaction solution by resin absorption, reduced the heavy metal content in the finished product, more definite is the heavy metal content in the finished product to be had be reduced to below the 10ppm more than the 80ppm, make finished product more meet the Chinese Pharmacopoeia regulation, more help health.Heavy metal refers generally to proportion greater than 5 metal, as gold and silver, copper, iron, lead etc.Because of this class ion pair human body is poisonous, the excessive people's of entering cognition causes heavy metal poisoning, and the harm kidney and other organs is so drug standard is to its finite quantity requirement.But require oral level raw material to answer≤20ppm as the song rutin, the injection raw material is answered≤10ppm.The method of pressing the Chinese Pharmacopoeia regulation usually detects.Heavy metal exists with ionic state in plant milk extract.Heavy metal in the troxerutin is mainly derived from the plant milk extract rutin, add resin and in the aqueous solution, drive away the micro heavy ion, be because resin has stronger adsorptivity, make heavy metal ion in the reaction solution, reduce the heavy metal content in the troxerutin finished product by resin absorption.
3. be that the etherification reaction product is the purpose product in the reaction of the synthetic troxerutin of raw material with rutin, and oxidation reaction product is the side reaction that produces by product.Oxidizing reaction is had katalysis is chemical general knowledge to transition metal ion in the aqueous solution.Reduced the speed that transition metal ion in the aqueous solution must reduce oxidizing reaction.Thereby reduce the generation of oxidized byproduct, reach the purpose that improves troxerutin content in the product.
3. the consumption that synthesizes the aqueous solvent of troxerutin in the aqueous solution of bibliographical information is 5 times of rutin total amount.Reaction needs and will obtain the exsiccant resultant after the moisture evaporation after finishing.Process need consumes energy and generation factory effluent with moisture evaporation.The present invention utilizes bimolecular nucleophilic reaction mechanism, adopts the gradation charging process, the aqueous solvent of reacting usefulness is reduced to be below 1.5 times of rutin total amount, preferred 1 times.Owing to reduced the water yield, thereby reduce the total amount of oxygen in reaction solution, and reached the purpose of the growing amount that reduces oxidized byproduct.
Embodiment:
Further specify the present invention below by embodiment.The preparation method who it should be understood that the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, and the simple modifications to preparation method of the present invention under design prerequisite of the present invention all belongs to the scope of protection of present invention.
Embodiment 1: the method for preparing troxerutin
Under 75 ℃, 100g rutin, 100g water, 0.82g sodium hydroxide are joined in the reactor, feed nitrogen flooding and remove oxygen; Feed oxyethane then, monitoring pH value of solution value when reacting liquid pH value is 9.1, reduces temperature of reaction to 60 ℃, adds resin 10g, continue to react to reacting liquid pH value be 10.0 o'clock, stop to add oxyethane.It is about 4.5 to add 1:1 aqueous hydrochloric acid regulator solution pH value, and heat filtering concentrates, vacuum-drying, the 120.5g troxerutin, wherein HPLC detects 3 ', 4 ', 7-Z 6000 content is 92.8%.
Embodiment 2: the method for preparing troxerutin
Under 75 ℃, 100g rutin, 150g water, 0.83g sodium hydroxide are joined in the reactor, feed oxyethane then, monitoring pH value of solution value, when reacting liquid pH value is 9.2, reduce temperature of reaction to 60 ℃, add resin 10g, continue to react to reacting liquid pH value be 10.1 o'clock, stop to add oxyethane.It is about 4.5 to add 1:1 aqueous hydrochloric acid regulator solution pH value, and heat filtering concentrates, vacuum-drying, the 121.2g troxerutin, wherein HPLC detects 3 ', 4 ', 7-Z 6000 content is 85.2%.
Embodiment 3: the method for preparing troxerutin
Under 75 ℃, 100g rutin, 200g water, 0.85g sodium hydroxide are joined in the reactor, feed oxyethane then, monitoring pH value of solution value, when reacting liquid pH value is 9.3, reduce temperature of reaction to 60 ℃, add resin 10g, continue to react to reacting liquid pH value be 10.2 o'clock, stop to add oxyethane.It is about 4.5 to add 1:1 aqueous hydrochloric acid regulator solution pH value, and heat filtering concentrates, vacuum-drying, the 120.4g troxerutin, wherein HPLC detects 3 ', 4 ', 7-Z 6000 content is 81.6%.
Claims (5)
1. one kind synthetic 3 ', 4 ', the method of 7-Z 6000, this method uses rutin and oxyethane to carry out ethoxyl etherification at sodium hydroxide under as the condition of catalyzer, it is characterized in that, in ethoxyl etherification, the weight ratio of rutin and water is 1:1～1:3, and the weight ratio of rutin and sodium hydroxide is 100:0.82～100:0.85; When the pH of reaction solution value is 9.0～9.5, add hydrogen type cation exchange resin; When the pH value of this reaction response liquid terminal point was 9.5～10.3, this reaction reached terminal point, added aqueous hydrochloric acid and came termination reaction, and making reaction solution final pH value is 4.0～5.0.
2. according to the process of claim 1 wherein that the weight ratio of rutin and water is 1:1～1:1.5.
3. according to the process of claim 1 wherein 3 ', 4 ' in the troxerutin crude product for preparing, 7-Z 6000 HPLC weight content is greater than 78%.
4. according to the method for claim 3,3 ', 4 ' in the troxerutin crude product that wherein prepares, the HPLC weight content of 7-Z 6000 is greater than 80%.
5. according to the method for claim 4,3 ', 4 ' in the troxerutin crude product that wherein prepares, the HPLC weight content of 7-Z 6000 is greater than 85%.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102924546A (en) * | 2012-11-08 | 2013-02-13 | 兰亚朝 | Preparation method of troxerutin |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101891784B (en) * | 2010-07-17 | 2012-02-15 | 山西津华晖星制药有限公司 | Method for synthesizing 3',4',7-troxerutin |
| CN104177461B (en) * | 2013-05-21 | 2016-11-09 | 济南新力特科技有限公司 | The preparation method of troxerutin |
| CN103601772B (en) * | 2013-11-12 | 2016-03-16 | 李玉山 | Ultrasonic assistant method synthesis troxerutin |
| KR101809943B1 (en) * | 2014-05-23 | 2017-12-18 | 지난 신라이트 테크놀로지 컴퍼니 리미티드 | Preparation method of trihydroxyethyl rutoside |
| CN106589017B (en) * | 2016-11-14 | 2019-10-29 | 重庆市碚圣医药科技股份有限公司 | The preparation method of 3 ', 4 ', 7- troxerutin |
| CN106892950B (en) * | 2017-03-02 | 2020-03-17 | 河南师范大学 | Preparation method of high-content troxerutin |
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| CN102924546A (en) * | 2012-11-08 | 2013-02-13 | 兰亚朝 | Preparation method of troxerutin |
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Owner name: TOPFOND PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: TIANFANG PHARMACEUTICAL CO., LTD., HENAN Effective date: 20141231 |
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Effective date of registration: 20141231 Address after: Zhumadian City, Henan province 463000 Guangming Road Yicheng District No. 2 Patentee after: TIANFANG PHARMACEUTICAL CO., LTD. Address before: 463000 No. 2 Guangming Road, Henan, Zhumadian Patentee before: Tianfang Pharmaceutical Co., Ltd., Henan |