CN116731092A - Preparation method of high-purity troxerutin - Google Patents
Preparation method of high-purity troxerutin Download PDFInfo
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- CN116731092A CN116731092A CN202310487306.3A CN202310487306A CN116731092A CN 116731092 A CN116731092 A CN 116731092A CN 202310487306 A CN202310487306 A CN 202310487306A CN 116731092 A CN116731092 A CN 116731092A
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- IKGXIBQEEMLURG-NVPNHPEKSA-N rutin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-NVPNHPEKSA-N 0.000 title claims abstract description 109
- 229960003232 troxerutin Drugs 0.000 title claims abstract description 87
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 84
- 238000000034 method Methods 0.000 claims abstract description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229960004555 rutoside Drugs 0.000 claims abstract description 26
- JMGZEFIQIZZSBH-UHFFFAOYSA-N Bioquercetin Natural products CC1OC(OCC(O)C2OC(OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5)C(O)C2O)C(O)C(O)C1O JMGZEFIQIZZSBH-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- IVTMALDHFAHOGL-UHFFFAOYSA-N eriodictyol 7-O-rutinoside Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C=C3C(C(C(O)=C(O3)C=3C=C(O)C(O)=CC=3)=O)=C(O)C=2)O1 IVTMALDHFAHOGL-UHFFFAOYSA-N 0.000 claims abstract description 25
- FDRQPMVGJOQVTL-UHFFFAOYSA-N quercetin rutinoside Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 FDRQPMVGJOQVTL-UHFFFAOYSA-N 0.000 claims abstract description 25
- ALABRVAAKCSLSC-UHFFFAOYSA-N rutin Natural products CC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5 ALABRVAAKCSLSC-UHFFFAOYSA-N 0.000 claims abstract description 25
- 235000005493 rutin Nutrition 0.000 claims abstract description 25
- 239000012043 crude product Substances 0.000 claims abstract description 15
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000005070 sampling Methods 0.000 claims abstract description 7
- 239000007791 liquid phase Substances 0.000 claims abstract description 5
- 238000005406 washing Methods 0.000 claims abstract description 3
- 238000002425 crystallisation Methods 0.000 claims description 22
- 230000008025 crystallization Effects 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 22
- 239000007788 liquid Substances 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000000047 product Substances 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- 239000012065 filter cake Substances 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- 238000002386 leaching Methods 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 238000007670 refining Methods 0.000 claims description 10
- 239000003651 drinking water Substances 0.000 claims description 9
- 235000020188 drinking water Nutrition 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 229960000583 acetic acid Drugs 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000008213 purified water Substances 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 4
- 238000003825 pressing Methods 0.000 claims description 4
- 238000004064 recycling Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000004042 decolorization Methods 0.000 claims description 3
- 238000001514 detection method Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 9
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 238000002156 mixing Methods 0.000 abstract description 2
- 238000004134 energy conservation Methods 0.000 abstract 1
- 238000001914 filtration Methods 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 5
- 239000003610 charcoal Substances 0.000 description 5
- 229940105082 medicinal charcoal Drugs 0.000 description 5
- 239000012535 impurity Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000007547 defect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000003298 dental enamel Anatomy 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000628997 Flos Species 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000003916 acid precipitation Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of high-purity troxerutin, which comprises the steps of mixing methanol, high-purity rutin, triethylamine and ethylene oxide, reacting at 70-100 ℃ under the pressure of 0.2-0.3 MPa, sampling liquid phase, detecting that the peak area of the troxerutin is maximum, ending the reaction, decoloring, crystallizing and washing to obtain a troxerutin crude product. The method disclosed by the invention has the advantages of simple process, low cost and easiness in obtaining used solvents, low toxicity, environment friendliness, energy conservation and environment friendliness, and the purity of the prepared troxerutin is more than 99%, so that the method is suitable for large-scale production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of high-purity troxerutin.
Background
Troxerutin is a mixture of 7, 3', 4' -tri-hydroxyethyl rutin, which is mainly used in the second edition 2015 of the pharmacopoeia of the people's republic of China (hereinafter referred to as the Chinese pharmacopoeia 2015), and is a capillary protective agent. 7, 3', 4' -Trioxyethyl rutin, chemical name 3', 4', 7-tris [ O- (2-hydroxyethyl) -5-hydroxyflavone-3 ] -rutin. The content of troxerutin raw material medicine in 2015 edition Chinese pharmacopoeia is defined as calculated according to anhydrous substance, and troxerutin content is not less than 80.0% (for oral administration) and 88.0% (for injection). Troxerutin has the advantages of good effect, high safety, low cost and the like. It is well known that impurities are the main factor causing adverse reactions of medicines, so that the purity of medicines is improved, the impurity content is reduced, and the method has important clinical significance.
At present, only a few patent reports are available for the process suitable for industrial production except that a few special preparation methods can realize the preparation of troxerutin with the content of more than 98.0%. Li Sai and the like firstly carry out hydroxyethylation reaction on rutin to prepare 7-mono-hydroxyethyl rutin with higher purity, then carry out hydroxyethylation on the 7-mono-hydroxyethyl rutin continuously, and finally obtain troxerutin with the content of more than 98.0% by desalting the obtained crude troxerutin with resin or removing impurities with macroporous resin. Extracting crude rutin from flos Sophorae Immaturus by alkali extraction and acid precipitation, dissolving with methanol, adding ammonia water, EDTA and sodium bisulphite reaction solution twice, decolorizing with active carbon, filtering, vacuum recovering methanol under reduced pressure, reacting with methanol and catalyst under normal pressure for 2 hr, cooling for crystallization, press filtering with plate and frame, separating and drying to obtain troxerutin with purity up to 99%. Li Xiaochang et al discloses a method for preparing high-purity troxerutin, wherein when troxerutin and ethylene oxide are subjected to a hydroxyethyl reaction under the condition of an alkaline catalyst, a specific complexing reaction is carried out on a certain node, so that the exposed 5-hydroxyl and 4-carbonyl in rutin molecules are masked, then the subsequent etherification is carried out, and acid hydrolysis is carried out after full reaction, so that troxerutin with high purity for injection is obtained after refining. Jiang Yuqin et al disclose a method for preparing high-purity troxerutin, which comprises the steps of obtaining high-purity troxerutin through acetylation protection and deprotection reaction, and then researching a novel process for preparing high-purity troxerutin by using a 3-generation polyamide-amine (PAMAM) dendritic polymer with stable weak alkalinity as a catalyst, wherein the purity reaches 98.6%.
However, in the prior art, the purification steps of rutin are more, the consumption of a solvent is high, the toxicity is high, the preparation process of high-purity troxerutin is complex, the yield is low, and the troxerutin cannot be truly applied to large-scale mass production. Aiming at the technical defects, a troxerutin preparation process which has the advantages of simplified synthesis process, simple operation, low solvent toxicity, low price, easy obtainment, high yield and suitability for large-scale production needs to be researched and developed.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a preparation method of troxerutin with high purity. The method has the advantages of simple process, low cost and easy obtainment of used solvents, low toxicity, environmental protection, and the purity of the prepared troxerutin is more than 99%, the yield is more than 88%, and the method is suitable for large-scale production.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a process for preparing high-purity troxerutin includes such steps as mixing methanol, high-purity rutin, triethylamine and ethylene oxide, reaction at 70-100 deg.C and 0.2-0.3 MPa, sampling liquid phase, detecting the maximum peak area of troxerutin, decoloring, crystallizing and washing.
The reaction scheme of the method of the invention is shown below.
Specifically, in the preparation method, 3-5 parts of methanol, 1 part of high-purity rutin, 0.01-0.02 part of triethylamine and 0.5-0.6 part of ethylene oxide can be mixed according to parts by weight.
Further, the decoloring is specifically as follows: and after the reaction is finished, adding 0.02-0.04 part of medicinal carbon, heating to 80-90 ℃ and refluxing for 50-70min for decoloring.
Further, the crystallization is specifically: after the decoloring is finished, the feed liquid is transferred to a crystallization tank through a filter. When the temperature of the feed liquid is reduced to 18-30 ℃, adding a proper amount of glacial acetic acid to adjust the pH (acidity) to 5.2-6.8, stirring and crystallizing 4-5 h, stopping stirring, carrying out solid-liquid separation, and leaching a filter cake by using methanol to obtain a troxerutin crude product.
In the preparation method of the high-purity troxerutin, the crude troxerutin can be refined and purified through the following steps:
1) Refining and dissolving: adding 3-4 parts by weight of 95% methanol, 0.3-0.5 part by weight of isopropanol and 0.7-0.9 part by weight of purified water into a reaction tank, adding 1 part by weight of troxerutin crude product and 0.03-0.04 part by weight of medicinal carbon, stirring and preserving heat for 50-70min under the conditions of controlling the temperature in the tank to 80-90 ℃ and the pressure to 0.1-0.2 MPa to dissolve materials, and pressing the material liquid into a crystallization tank through a filter;
2) Refining and crystallizing: when the temperature of the feed liquid in the crystallization tank is reduced to 18-30 ℃, adding a proper amount of glacial acetic acid to adjust the pH to 5.2-6.8, stirring and crystallizing 4-5. 5 h, stopping stirring, carrying out solid-liquid separation, leaching a filter cake by using methanol to obtain a high-purity troxerutin wet product, and drying to obtain a high-purity troxerutin dry product.
Further, the drying in step 2) is specifically: and (3) placing the high-purity troxerutin wet product in a vacuum dryer, and preserving the temperature for 2-3 hours at the temperature of 110-120 ℃ and the vacuum degree of-0.06 to-0.092 MPa to obtain the high-purity troxerutin dry product.
In the preparation method of the high-purity troxerutin, the high-purity troxerutin is obtained by purifying the following steps: adding 1 part of crude rutin (the content of which is more than 95 percent) into a reaction kettle, adding 4-6 parts of ethyl acetate-methanol mixed solution and 0.02-0.05 part of medicinal carbon, refluxing and decoloring at 80-90 ℃ for 50-70min, transferring the mixture into a crystallization tank containing 0.5-0.8 part of drinking water through a filter, stirring and crystallizing at 18-30 ℃ for 4-6 hours, centrifuging, recycling filtrate, leaching a filter cake by using the drinking water, and drying at 100-110 ℃ for 4-6 hours to obtain high-purity rutin with the content of more than 98 percent.
Further, in the mixed solution of ethyl acetate and methanol, the volume ratio of ethyl acetate to methanol can be 2-3:1.5, preferably 2.5:1.5.
aiming at the defects existing in the prior art, the method simplifies the operation by optimizing the purification and synthesis process, screens the solvents with low toxicity and low cost and availability, prepares the troxerutin with high purity, and can protect the health of production personnel. Compared with other prior art, the process of the invention has realized hundred kilogram level mass production, the product quality purity is confirmed by national level of China's standards institute, and the process is applied to the calibration of troxerutin standard, after the standard used in domestic circulation is produced by the method, the process is used for producing the standard with China's standards institute, thereby effectively ensuring the market supply of troxerutin standard, and having great social value.
The preparation process of the high-purity troxerutin is simple, the investment is less, the used solvent is cheap and easy to obtain, the toxicity is low, the environment is protected, and the troxerutin is environment-friendly and suitable for mass production. According to the method, troxerutin with purity higher than 99% is finally obtained under the action of stable weak alkaline triethylamine serving as a catalyst through rutin purification, and the yield is higher than 88%, so that the method can be used for mass production. The key technical points of the invention are as follows: 1) Using cheap and easily available solvent, and selecting triethylamine with stable weak alkalinity as a catalyst;
2) Purifying rutin by using a mixed solvent of methanol and ethyl acetate, adding drinking water in the crystallization process to increase the polarity of the solution, and improving the solubility of different impurities to achieve the purification purpose;
3) And (3) refining troxerutin by using a mixed solvent of methanol-isopropanol-purified water, and crystallizing the troxerutin preferentially to improve the purity of the product.
Compared with the prior art, the method has the following beneficial effects:
the invention simplifies the purification steps and treatment difficulty of rutin, uses cheap and easily available solvents for production, can recycle the solvents, can recycle the mother liquor for the second time, saves resources, has less waste production, is favorable for environmental protection and meets the requirement of green development. The invention provides a novel high-purity troxerutin purification method suitable for industrial production, which is simple to operate, and the troxerutin with purity higher than 99% is finally obtained, and the yield is higher than 88%.
Drawings
FIG. 1 is a chart showing the purity of troxerutin obtained in example 2.
Detailed Description
The following describes the technical scheme of the present invention in further detail with reference to examples, but the scope of the present invention is not limited thereto.
In the examples below, the starting materials used were all commercially available products which were commercially available as they are. Unless otherwise indicated, parts are all parts by weight.
Example 1
A preparation method of high-purity troxerutin comprises the following steps:
step 1, rutin purification
Adding 1 part of crude rutin (the content of which is more than 95 percent) into a reaction kettle, adding 5 parts of ethyl acetate-methanol mixed solution (the volume ratio of ethyl acetate to methanol is 2.5:1.5) and 0.02 part of medicinal charcoal, refluxing and decoloring for 1 hour at 88 ℃, transferring the mixture into a crystallization tank containing 0.5 part of drinking water through a filter, stirring and crystallizing for 4 hours at 25 ℃, centrifuging after crystallization is finished, recycling filtrate, leaching a filter cake by using the drinking water, and then placing the filter cake into a hot air circulation oven for drying for 4 hours at 105 ℃ to obtain high-purity rutin with the content of more than 98 percent.
Step 2, synthesizing a troxerutin crude product
3 parts of methanol is pumped into a stainless steel reaction tank, 1 part of high-purity rutin and 0.01 part of triethylamine are added, a tank cover is closed, 0.5 part of ethylene oxide is introduced, heating is started after the end, the reaction is performed under the conditions that the temperature in the tank is 85 ℃ and the pressure is 02-0.3MPa, sampling is performed through a sampling port, and the reaction is finished when the peak area of the liquid phase detection troxerutin is maximum (about 4 hours is needed). Pressing into enamel reactor. 0.02 part of medicinal charcoal is added, heated to 80 ℃ and refluxed for 1 hour for decolorization. After the decoloring is finished, the feed liquid is transferred to a crystallization tank through a filter. When the temperature of the feed liquid is reduced to about 25 ℃, adding a proper amount of glacial acetic acid to adjust the pH to about 6.0, stirring and crystallizing for 4 hours, stopping stirring, filtering and separating, leaching a filter cake with 0.5 times of methanol to obtain a crude product of troxerutin, wherein the content of the crude product of troxerutin is 92%, and the yield is 97%.
And 3, refining and dissolving: 3 parts of 95% methanol, 0.3 part of isopropanol and 0.7 part of purified water are pumped into a reaction tank, and 1 part of troxerutin crude product and 0.03 part of medicinal charcoal are added. Heating is started, stirring and heat preservation are carried out for 1 hour under the conditions that the temperature in the tank is controlled to be 85 ℃ and the pressure is controlled to be 0.1-0.2 MPa, and the feed liquid is pressed into the crystallization tank through the filter.
And step 4, refining and crystallizing: when the temperature of the feed liquid in the crystallization tank is reduced to about 25 ℃, adding a proper amount of glacial acetic acid to adjust the pH to about 6.0, stirring and crystallizing for 4 hours, stopping stirring, filtering and separating, and leaching the filter cake with 0.5 times of methanol to obtain the high-purity troxerutin wet product. And (3) placing the high-purity troxerutin wet product in a vacuum dryer, and preserving the temperature for 2 hours under the conditions of controlling the temperature to 115 ℃ and the vacuum degree to-0.06 to-0.07 MPa to obtain the high-purity troxerutin dry product, wherein the purity is 99.2 percent and the yield is 91 percent.
Example 2
A preparation method of high-purity troxerutin comprises the following steps:
step 1, rutin purification
Adding 1 part of crude rutin (the content of which is more than 95 percent) into a reaction kettle, adding 5 parts of ethyl acetate-methanol mixed solution (the volume ratio of ethyl acetate to methanol is 2.5:1.5) and 0.04 part of medicinal carbon, refluxing and decoloring for 1 hour at 83 ℃, transferring the mixture into a crystallization tank containing 0.8 part of drinking water through a filter, stirring and crystallizing for 5 hours at 20 ℃, centrifuging after crystallization is finished, recycling filtrate, leaching a filter cake by using the drinking water, and then placing the filter cake into a hot air circulation oven for drying for 5 hours at 105 ℃ to obtain high-purity rutin with the content of more than 98 percent.
Step 2, synthesizing a troxerutin crude product
According to parts by weight, 5 parts of methanol is pumped into a stainless steel reaction tank, 1 part of high-purity rutin and 0.02 part of triethylamine are added, a tank cover is closed, 0.6 part of ethylene oxide is introduced, after the end, heating is started, the reaction is performed under the conditions that the temperature in the tank is 95 ℃ and the pressure is 02-0.3MPa, sampling is performed through a sampling port, and the reaction is finished when the peak area of the liquid phase detection troxerutin is maximum (about 4.3 hours is needed). Pressing into enamel reactor. 0.04 parts of medicinal charcoal is added, heated to 85 ℃ and refluxed for 1 hour for decolorization. After the decoloring is finished, the feed liquid is transferred to a crystallization tank through a filter. When the temperature of the feed liquid is reduced to about 20 ℃, adding a proper amount of glacial acetic acid to adjust the pH to about 6.3, stirring and crystallizing for 4 hours, stopping stirring, filtering and separating, leaching a filter cake with 0.5 time of methanol to obtain a crude product of troxerutin, wherein the content of the crude product of troxerutin is 93%, and the yield is 96%.
And 3, refining and dissolving: 3 parts of 95% methanol, 0.5 part of isopropanol and 0.8 part of purified water are pumped into a reaction tank, and 1 part of troxerutin crude product and 0.04 part of medicinal charcoal are added. Heating is started, stirring and heat preservation are carried out for 1 hour under the conditions that the temperature in the tank is controlled to be 85 ℃ and the pressure is controlled to be 0.1-0.2 MPa, and the feed liquid is pressed into the crystallization tank through the filter.
And step 4, refining and crystallizing: when the temperature of the feed liquid in the crystallization tank is reduced to about 20 ℃, adding a proper amount of glacial acetic acid to adjust the pH to about 6.3, stirring and crystallizing for 4 hours, stopping stirring, filtering and separating, and leaching the filter cake with 0.5 times of methanol to obtain the high-purity troxerutin wet product. And (3) placing the high-purity troxerutin wet product in a vacuum dryer, and preserving the temperature for 2 hours under the conditions of 115 ℃ and a vacuum degree of-0.07 to-0.08 MPa to obtain the high-purity troxerutin dry product with the purity of 99% (see figure 1) and the yield of 90%.
Claims (8)
1. A preparation method of high-purity troxerutin is characterized in that methanol, high-purity rutin, triethylamine and ethylene oxide are mixed and reacted at the temperature of 70-100 ℃ and the pressure of 0.2-0.3 MPa, the reaction is finished when the peak area of the troxerutin is maximum by sampling liquid phase detection, and a troxerutin crude product is obtained by decoloring, crystallizing and washing.
2. The process for preparing troxerutin of high purity according to claim 1, wherein 3-5 parts by weight of methanol, 1 part by weight of troxerutin of high purity, 0.01-0.02 part by weight of triethylamine and 0.5-0.6 part by weight of ethylene oxide are mixed.
3. The method for preparing high-purity troxerutin according to claim 2, wherein the decolorization is specifically as follows: and after the reaction is finished, adding 0.02-0.04 part of medicinal carbon, heating to 80-90 ℃ and refluxing for 50-70min for decoloring.
4. The method for preparing high-purity troxerutin according to claim 3, wherein the crystallization is specifically: after the decoloring is finished, transferring the feed liquid to a crystallization tank through a filter, after the temperature of the feed liquid is reduced to 18-30 ℃, adding a proper amount of glacial acetic acid to adjust the pH to 5.2-6.8, stirring and crystallizing 4-5 h, performing solid-liquid separation, and leaching a filter cake with methanol to obtain a troxerutin crude product.
5. The method for preparing high-purity troxerutin according to claim 1, wherein the troxerutin crude product is refined and purified by the following steps:
1) Refining and dissolving: adding 3-4 parts by weight of 95% methanol, 0.3-0.5 part by weight of isopropanol and 0.7-0.9 part by weight of purified water into a reaction tank, adding 1 part by weight of troxerutin crude product and 0.03-0.04 part by weight of medicinal carbon, stirring and preserving heat for 50-70min under the conditions of controlling the temperature in the tank to 80-90 ℃ and the pressure to 0.1-0.2 MPa, and pressing the feed liquid into a crystallization tank through a filter;
2) Refining and crystallizing: when the temperature of the feed liquid in the crystallization tank is reduced to 18-30 ℃, adding a proper amount of glacial acetic acid to adjust the pH to 5.2-6.8, stirring and crystallizing 4-5. 5 h, separating solid from liquid, leaching a filter cake with methanol to obtain a high-purity troxerutin wet product, and drying to obtain a high-purity troxerutin dry product.
6. The method for preparing high-purity troxerutin according to claim 5, wherein said drying in step 2) is specifically: and (3) placing the high-purity troxerutin wet product in a vacuum dryer, and preserving the temperature for 2-3 hours at the temperature of 110-120 ℃ and the vacuum degree of-0.06 to-0.092 MPa to obtain the high-purity troxerutin dry product.
7. The method for preparing high-purity troxerutin according to claim 1, wherein the high-purity troxerutin is obtained by purification through the steps of: adding 1 part of crude rutin into a reaction kettle, adding 4-6 parts of ethyl acetate-methanol mixed solution and 0.02-0.05 part of medicinal carbon, refluxing and decoloring at 80-90 ℃ for 50-70min, transferring into a crystallization tank containing 0.5-0.8 part of drinking water through a filter, stirring and crystallizing at 18-30 ℃ for 4-6 hours, centrifuging, recycling filtrate, leaching a filter cake by using the drinking water, and drying at 100-110 ℃ for 4-6 hours to obtain high-purity rutin with the content of more than 98%.
8. The method for preparing high-purity troxerutin according to claim 7, wherein the volume ratio of ethyl acetate to methanol in the ethyl acetate-methanol mixed solution is 2-3:1.5.
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