CN1651394A - Method of preparing diacetyl parietic acid from rhubarb extract - Google Patents
Method of preparing diacetyl parietic acid from rhubarb extract Download PDFInfo
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- CN1651394A CN1651394A CN 200410065377 CN200410065377A CN1651394A CN 1651394 A CN1651394 A CN 1651394A CN 200410065377 CN200410065377 CN 200410065377 CN 200410065377 A CN200410065377 A CN 200410065377A CN 1651394 A CN1651394 A CN 1651394A
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- rhizoma rhei
- diacetyl rhein
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Abstract
A process for preparing diacetylchrysophanic acid from the extract of rhubab (chrysophanic acid, chrysophanol, or aloe-emodin) includes such steps as acetylating, oxidizing, removing Cr, ammonizing, conversing, acidifying, recrystallizing and drying. Said product can be used for treating osteoarthritis.
Description
Technical field
The present invention relates to a kind of method for preparing diacetyl rhein by Radix Et Rhizoma Rhei extract.
Background technology
Diacerein was gone on the market by French Ni Gema company (Laboratoires.Negma) in 1994, its commodity " An Biding " by name (artodar), Italian subsequently holy Martino Si Kemaluoao. Synteco S.P.A., Cologne, Germany Madaus AG, U.S. Xin Kai company (Cinkate) etc. successively go into operation and go on the market.But domestic still do not have this product of manufacturer production so far, and " An Biding " of use is imported product.
Diacetyl rhein is owing to the resource difference of various countries, and its synthetic starting raw material also is not quite similar.Producing this product in the world is to be starting raw material with the sennae at first, for example connection group's German Patent CN1088907A, CN1088571A, and after extracting the cassia angustifolia glucoside, again through hydrolysis, oxidation, acetylize and getting.The aloe that more American-European countries use South Africa instead is that starting raw material is produced this product, they are extract Barbaloin in aloe after, obtain diacetyl rhein through oxydrolysis, this operational path subject matter is the difficult control of rhabarberone residual in the finished product, is easy to exceed standard.In addition, also the someone attempts to carry out artificial chemosynthesis, but because route is long, and cost is too high and fail to realize suitability for industrialized production.Rheum officinale is the often Chinese medicinal materials of a kind of wide material sources of use of China, adopts the starting raw material of rheum officinale as diacetyl rhein, helps the development and use of China's existing resource.
Summary of the invention
The objective of the invention is to: the method that is prepared diacetyl rhein by Radix Et Rhizoma Rhei extract is provided, and the rheum officinale that makes full use of China's abundant is that starting raw material is produced diacetyl rhein.Owing to contain a large amount of anthraquinones in the rheum officinale, in plant such as sorrel, the Rheum officinale rhizome, be that principal mode exists mainly in the anthraquinone compounds that is contained especially with rhubarb yellow, chrysophanol and glucoside thereof.These anthraquinones that extracted by rheum officinale are after isolating Schuttgelb and rheochrysidin, and remaining rhubarb yellow chrysophanol and rhabarberone mixture can be used as the raw materials for production of diacetyl rhein.
Technical solution of the present invention is: prepare diacetyl rhein by Radix Et Rhizoma Rhei extract; its domestic animal is levied and is: the rhubarb anthraquinone compound that extracts with rheum officinale is that the mixture of rhubarb yellow, chrysophanol, rhabarberone is a raw material, prepares the oxalic acid rhubarb yellow through acetylize, oxidation, dechromisation, amination, conversion, acidifying, recrystallization, drying process step.
Processing step is as follows:
Acetylation: use aceticanhydride as acetylizing agent; Glacial acetic acid potassium, sodium acetate, anhydrous, pyridine or picoline are as catalyzer; the weight ratio of raw material and aceticanhydride is 1: 10～20; the acetylization reaction temperature is 50～100 ℃; time is 1.0h～2.0h, and catalyst levels is 0.3～1.8 times of raw material.
Oxidising process: use the chromium trioxide acetum as oxygenant, the weight ratio of chromium trioxide and raw material is 1: 0.7～1.2,50～70 ℃ of oxidizing reaction temperatures, and the time is 3h～4h.
Dechromisation process: use disodium ethylene diamine tetraacetate as complexing agent, the mol ratio of disodium ethylene diamine tetraacetate and chromium trioxide 1: 0.5～1.2.
The amination process: use triethylamine as aminating agent, the weight ratio of raw material and triethylamine is 1: 2～3.
Conversion process: use Potassium ethanoate as the salify transforming agent, the weight ratio of raw material and Potassium ethanoate is: 1: 0.8～1.0.
Acidization: use mineral acid, comprise sulfuric acid, hydrochloric acid or phosphoric acid.
Recrystallization process: use Glacial acetic acid or 1.4-dioxane as solvent, the weight ratio of raw material and solvent is 1: 30～40.
Drying process: be under normal temperature or vacuum condition, temperature is 40～80 ℃, and the time is 4～12h.
Radix Et Rhizoma Rhei extract is the mixture of rhubarb yellow, chrysophanol, rhabarberone, and part by weight is 0～100: 0～100: 0～100.
Diacetyl rhein (diacetylrhein), commodity by name " diacerein " (diacerein) or be " An Biding " (artodar).Chemistry diacetyl dihydroanthracene carboxylic acid (1.8-Diacetoxy-3-cardoxyanthraquinane) by name.This product is a kind of new interleukin-11 β (IL-1 β) inhibitor, also is that the anthraquinone class of going on the market is in recent years treated one of specific drugs of osteoarthritis (being called for short OA).
Advantage of the present invention is:
(1) starting raw material of this production diacetyl rhein is the plant rheum officinale, and the source is abundant, and price is low.
(2) production process is to be raw material with the Radix Et Rhizoma Rhei extract, promptly uses the mixture of rhubarb yellow, chrysophanol, rhabarberone, has saved monomeric separation operation process, has promptly improved total yield of products, has reduced production cost again.
Embodiment
Embodiment 1
(1) will contain in 38 milliliters of acetic anhydride of mixture (4: 5: 1) 2.1 gram addings of rhubarb yellow, chrysophanol and rhabarberone, and stir and placed 10 minutes;
(2) in reaction solution, add 2.1 gram sodium acetate, anhydrouss again, heat temperature raising to 95 ℃, stirring reaction 90 minutes, filtered while hot, crystallisation by cooling filters, washing, the diacetylation compound;
(3) the diacetylation compound that obtains is joined in 120 milliliters of Glacial acetic acid-acetic anhydride (10: 1) mixed solution, be warming up to 50 ℃, begin to drip 64 milliliters of chromium trioxide solution (2.2 gram chromium trioxides are dissolved in 4 ml deionized water, add 60 milliliters in Glacial acetic acid again), after dripping end, 60～65 ℃ of following insulation reaction 3 hours, again oxidation liquid to be poured in the frozen water, faint yellow precipitation is separated out, filter, washing, drying obtains the diacetyl rhein crude product;
(4) the diacetyl rhein crude product is added (acetone: water=20: 1) in 25 milliliters of acetone and the deionized water mixed solution, at room temperature stirred 10-15 minute, make its homogenizing, heat up 40-45 ℃ then, and add 16 milliliters of acetone-triethylamine mixed solution (1: 1) again, fully stir and make it form diacetyl rhein amine salt solution, elimination solid impurity;
(5) 1.0 times of Powdered Potassium ethanoates of adding material quantity in filtrate after 0.5 hour, are cooled to 10 ℃ with reaction solution at 60 ℃ of following stirring reactions, place crystallization 1h, leach diacetyl rhein sylvite, use washing with acetone again;
(6) sylvite stirring and dissolving in ionized water again, and add disodium ethylene diamine tetra-acetic acid solution, use 33%H then
2SO
4PH reaches 3～5, be cooled to 10 ℃, and arrive neutral with deionized water wash, obtain the diacetyl rhein product 60-80 ℃ of following drying, use 30 times Glacial acetic acid to carry out recrystallization resulting product, and add 0.4 gram gac and decolour, diacetyl rhein content is 98.0% in the product, and yield is 82.5%.
Embodiment 2
(1) will contain in 38 milliliters of acetic anhydride of mixture (4: 6: 1) 2.1 gram addings of rhubarb yellow, chrysophanol and rhabarberone, and stir and placed 10 minutes;
(2) in reaction solution, add 0.8 gram Glacial acetic acid potassium again, heat temperature raising to 95 ℃, stirring reaction 90 minutes, filtered while hot, crystallisation by cooling filters, washing, the diacetylation compound;
(3) the diacetylation compound that obtains is joined in 120 milliliters of Glacial acetic acid-acetic anhydride (10: 1) mixed solution, be warming up to 50 ℃, begin to drip 64 milliliters of chromium trioxide solution (2.2 gram chromium trioxides are dissolved in 4 ml deionized water, add 60 milliliters in Glacial acetic acid again), after dripping end, 60～65 ℃ of following insulation reaction 3 hours, again oxidation liquid to be poured in the frozen water, faint yellow precipitation is separated out, filter, washing, drying obtains the diacetyl rhein crude product;
(4) the diacetyl rhein crude product is suspended in 120 milliliters 50% ethanol, and adds 2.1 gram Glacial acetic acid potassium and disodium ethylene diamine tetra-acetic acid solutions again, 80 ℃ of following stirring reactions 2 hours, dissolving was filtered and is obtained the diacetyl rhein potassium salt soln;
(5) potassium salt soln is transferred pH to 3～5 with 6% phosphoric acid solution, obtain the diacetyl rhein yellow mercury oxide, be washed to neutrality, dry down at 80 ℃, use 30 times Glacial acetic acid to carry out recrystallization resulting product, and add 0.4 the gram gac decolour, diacetyl rhein content is 97.8% in the product, yield is 80.8%.
Embodiment 3
(1) will contain chrysophanol and and rhabarberone mixture (5: 1) 2.8 gram add in the mixed solution (10: 1) of 60 milliliters of acetic anhydride and pyridine, reacted 2 hours down at 50 ℃, reactant is poured in the taper of the tool plug that fills 150 milliliters of cold water, and place mixture of ice and water to cool off the taper, crystallization, suction filtration is separated out yellow crystal, obtains the diacetylation compound;
(2) the diacetylation compound that obtains is dissolved in 120ml Glacial acetic acid-acetic anhydride mixed solution (10: 1); (3.3 gram chromium trioxides are dissolved in 5 ml deionized water to drip 70 milliliters of chromium trioxide solution about 50 ℃; add 65 milliliters in Glacial acetic acid again), added in about 30 minutes.Be warmed up to 60-65 ℃ after adding and continue stirring reaction 4h, and then the sap green reaction solution is added to crystallization in 800 milliliters of ice-cold deionized waters that contain disodium ethylene diamine tetraacetate.After treating that product is separated out fully, suction filtration, washing, drying;
(3) the diacetyl rhein crude product is added (acetone: water=20: 1) in 25 milliliters of acetone and the deionized water mixed solution, at room temperature stirred 10-15 minute, make its homogenizing, heat up 40-45 ℃ then, and add 15 milliliters of acetone-triethylamine mixed solution (1: 1) again, fully stir and make it form diacetyl rhein amine salt solution, elimination solid impurity;
(4) 1.0 times of Powdered Potassium ethanoates of adding material quantity in filtrate after 0.5 hour, are cooled to reaction solution 10 ℃ at 60 ℃ of following stirring reactions again, place crystallization 1 hour, leach diacetyl rhein sylvite, use washing with acetone again;
(5) diacetyl rhein sylvite dissolves in deionized water for stirring again, and adds disodium ethylene diamine tetra-acetic acid solution, uses 33%H then
2SO
4Transfer pH to reach 3～5, be cooled to 10 ℃, and arrive neutral with deionized water wash, obtain the diacetyl rhein product 60-80 ℃ of following drying, use 30 times Glacial acetic acid to carry out recrystallization resulting product, and add 0.4 the gram gac decolour, diacetyl rhein content is 97.4% in the product, yield is 81.7%.
Embodiment 4
(1) will contain chrysophanol and and rhabarberone mixture (4: 1) 2.8 gram add in the mixed solution (10: 1) of 60 milliliters of acetic anhydride and pyridine, reacted 2 hours down at 50 ℃, reactant is poured in the taper of the tool plug that fills 150 milliliters of cold water, and place mixture of ice and water to cool off the taper, crystallization, suction filtration is separated out faint yellow crystallization, obtains the diacetylation compound;
(2) the diacetylation compound that obtains is dissolved in 120ml Glacial acetic acid-acetic anhydride mixed solution (10: 1); (3.3 gram chromium trioxides are dissolved in 5 ml deionized water to drip 70 milliliters of chromium trioxide solution about 50 ℃; add 65 milliliters in Glacial acetic acid again), added in about 30 minutes.Be warmed up to 60-65 ℃ after adding and continue stirring reaction 4h, and then the sap green reaction solution is added to crystallization in 800 milliliters of ice-cold deionized waters that contain disodium ethylene diamine tetraacetate.After treating that product is separated out fully, suction filtration, washing, drying;
(3) the diacetyl rhein crude product is added (acetone: water=20: 1) in 25 milliliters of acetone and the deionized water mixed solution, at room temperature stirred 10-15 minute, make its homogenizing, heat up 40-45 ℃ then, and add 15 milliliters of acetone-triethylamine mixed solution (1: 1) again, fully stir and make it form diacetyl rhein amine salt solution, elimination solid impurity;
(4) 1.0 times of Powdered Potassium ethanoates of adding material quantity in filtrate after 0.5 hour, are cooled to reaction solution 10 ℃ at 60 ℃ of following stirring reactions again, place crystallization 1 hour, leach diacetyl rhein sylvite, use washing with acetone again;
(5) diacetyl rhein sylvite dissolves in deionized water for stirring again, and adds disodium ethylene diamine tetra-acetic acid solution, uses 33%H then
2SO
4Transfer pH to reach 3～5, be cooled to 10 ℃, and arrive neutral with deionized water wash, obtain the diacetyl rhein product 60-80 ℃ of following drying, use 30 times Glacial acetic acid to carry out recrystallization resulting product, and add 0.5 the gram gac decolour, diacetyl rhein content is 97.3% in the product, yield is 80.9%.
Embodiment 5
(1) takes by weighing mixture (1: 1) 2.2 grams that contain rhubarb yellow and chrysophanol and add in 38 milliliters of acetic anhydride stirring and dissolving 10 minutes;
(2) in reaction solution, add 1.2 gram Glacial acetic acid potassium again, heat temperature raising to 90～95 ℃, stirring reaction 1.5 hours, filtered while hot, wash, the diacetylation compound;
(3) the diacetylation compound that obtains is dissolved in 120 milliliters of Glacial acetic acid-acetic anhydride (10: 1) mixed solution, be warming up to 50 ℃, begin to drip 54 milliliters of chromium trioxide solution (2.0 gram chromium trioxides are dissolved in 4 ml deionized water, add 50 milliliters in Glacial acetic acid again), drip and finish the back at 60～65 ℃ of following insulation reaction 3h, again oxidation liquid is poured in the frozen water, faint yellow precipitation is separated out, and filters washing, drying obtains the diacetyl rhein crude product;
(4) the diacetyl rhein crude product is suspended in 130 milliliters 50% ethanol, and adds 2.1 gram Glacial acetic acid potassium again, 80 ℃ of following stirring reactions 2 hours, dissolving was filtered and is obtained potassium salt soln;
(5) potassium salt soln is transferred pH to 3～5 with 6% phosphoric acid solution, obtain the diacetyl rhein yellow mercury oxide, be washed to neutrality, drying is 2 hours under 80 ℃, use 30 times Glacial acetic acid to carry out recrystallization resulting product, and add 0.4 the gram gac decolour, diacetyl rhein content is 97.6% in the product, yield is 83.4%.
Claims (10)
1, prepared the method for diacetyl rhein by Radix Et Rhizoma Rhei extract, it is characterized in that: this method is raw material with the Radix Et Rhizoma Rhei extract, comprises following processing step: acetylize, oxidation, dechromisation, amination, conversion, acidifying, recrystallization, drying.
2, the method for preparing diacetyl rhein by Radix Et Rhizoma Rhei extract according to claim 1, it is characterized in that: Radix Et Rhizoma Rhei extract is two or three mixture in rhubarb yellow, chrysophanol, the rhabarberone, and part by weight is 0～100: 0～100: 0～100.
3, the method for preparing diacetyl rhein by Radix Et Rhizoma Rhei extract according to claim 1; it is characterized in that: acetylation uses aceticanhydride as acetylizing agent; Glacial acetic acid potassium, sodium acetate, anhydrous, pyridine or picoline are as catalyzer; the weight ratio of raw material and aceticanhydride is 1: 10～20; the acetylization reaction temperature is 50～100 ℃; time is 1.0h～2.0h, and catalyst levels is 0.3～1.8 times of raw material.
4, the method for preparing diacetyl rhein by Radix Et Rhizoma Rhei extract according to claim 1, it is characterized in that: oxidising process uses the chromium trioxide acetum as oxygenant, the weight ratio of chromium trioxide and raw material is 1: 0.7～1.2, oxidizing reaction temperature is 50～70 ℃, and the time is 3h～4h.
5, the method for preparing diacetyl rhein by Radix Et Rhizoma Rhei extract according to claim 1, it is characterized in that: the dechromisation process uses disodium ethylene diamine tetraacetate EDTA as complexing agent, the mol ratio of disodium ethylene diamine tetraacetate EDTA and chromium trioxide 1: 0.5～1.2.
6, according to claim 1ly prepare the method for diacetyl rhein by Radix Et Rhizoma Rhei extract, it is characterized in that: the amination process uses the triethylamine acetone soln as aminating agent, and the weight ratio of raw material and triethylamine is 1: 2～3.
7, according to claim 1ly prepare the method for diacetyl rhein by Radix Et Rhizoma Rhei extract, it is characterized in that: conversion process uses Potassium ethanoate as the salify transforming agent, and the weight ratio of raw material and Potassium ethanoate is 1: 0.8～1.0.
8, according to claim 1ly prepare the method for diacetyl rhein by Radix Et Rhizoma Rhei extract, it is characterized in that: acidization is used mineral acid, comprises sulfuric acid, hydrochloric acid, phosphoric acid.
9, according to claim 1ly prepare the method for diacetyl rhein by Radix Et Rhizoma Rhei extract, it is characterized in that: recrystallization process uses Glacial acetic acid or 1.4-dioxane as solvent, and the weight ratio of raw material and solvent is 1: 30～40.
10, according to claim 1ly prepare the method for diacetyl rhein by Radix Et Rhizoma Rhei extract, it is characterized in that: drying process is under normal temperature or vacuum condition, and temperature is 40～80 ℃, and the time is 4～12h.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100450990C (en) * | 2006-03-31 | 2009-01-14 | 江阴南极星生物制品有限公司 | Method for treating asphalt like slag in preparing rheinic acid and diacerein process with aloe |
| CN101104583B (en) * | 2006-07-13 | 2010-06-02 | 上海朴颐化学科技有限公司 | Technique for preparing diacerein by two-step oxidation process |
| CN104292101A (en) * | 2014-09-18 | 2015-01-21 | 上海慈瑞医药科技有限公司 | Preparation method of diacerein |
-
2004
- 2004-11-30 CN CN 200410065377 patent/CN1651394A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100450990C (en) * | 2006-03-31 | 2009-01-14 | 江阴南极星生物制品有限公司 | Method for treating asphalt like slag in preparing rheinic acid and diacerein process with aloe |
| CN101104583B (en) * | 2006-07-13 | 2010-06-02 | 上海朴颐化学科技有限公司 | Technique for preparing diacerein by two-step oxidation process |
| CN104292101A (en) * | 2014-09-18 | 2015-01-21 | 上海慈瑞医药科技有限公司 | Preparation method of diacerein |
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