CN104292101A - Preparation method of diacerein - Google Patents
Preparation method of diacerein Download PDFInfo
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- CN104292101A CN104292101A CN201410476405.2A CN201410476405A CN104292101A CN 104292101 A CN104292101 A CN 104292101A CN 201410476405 A CN201410476405 A CN 201410476405A CN 104292101 A CN104292101 A CN 104292101A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
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Abstract
The invention provides a preparation method of diacerein. The preparation method is characterized by comprising the following specific steps: putting rhein, a catalyst, a solvent and an acetylation reagent into a reaction container, wherein the catalyst is one or a combination of more than two of methanesulfonic acid, boric acid, aluminum trichloride, phosphoric acid and trifluoroacetic acid; the solvent is one or a combination of more than two of ethyl acetate, glycol dimethyl ether, N, N-dimethyl formamide, N, N-dimethyl acetamide, 1, 4-dioxane and methyl tert-butyl ether; heating in a stirring state for performing a reflux reaction for 6-24 hours; after the reaction is finished, reducing the temperature of the reaction liquid to 25+/-5 DEG C, performing suction filtration, recrystallizing the filter cake by use of the 1, 4-dioxane to obtain faint yellow powdery solid diacerein. The preparation method of the diacerein has the advantages that the product yield and the product purity are high, and no catalyst is residual in the product; the preparation method is convenient to operate and simple in after-treatment; meanwhile, the key quality problem of heavy metal exceeding in the product is solved.
Description
Technical field
The present invention relates to a kind of preparation method of diacetyl rhein, belong to chemosynthesis technical field.
Background technology
Diacetyl rhein (Diacerhein), have another name called diacerein (chemical name: 4,5-diacetyl-9,10-dihydro-9,10-dioxy-2-anthracene carboxylic acid) by suppressing the expression of osteogenic cell RANKL or suppressing generation and the release of Interleukin-1β and oxyradical, fundamentally treat the diseases such as degenerative osteoarthritis.Can generate, there is pain relieving, anti-inflammatory and antipyretic effect by inducing cartilage simultaneously, do not suppress prostaglandin(PG) to synthesize, osteoarthritis is had to the effect delaying disease process.
The correlative study of diacetyl rhein is a lot, and wherein preparation method mainly contains total synthesis method and semisynthesis.
The total synthesis method of diacetyl rhein is by R.Eder and C.Widmer (Helv.Chim.Acta5,3,1922 the earliest; 64191923) propose with 3-nitrophthalic acid acid anhydride method synthesis chrysophanol; again chrysophanol acetylize and oxidation are obtained diacerein; mainly with 3-nitrophthalic acid acid anhydride and meta-cresol for starting raw material; through Fu Ke (Friedel-Crafts) reaction, diacerein is prepared in reduction, condensation, diazotization, acetylize and oxidation.
This is first and has reported the important literature of complete synthesis chrysophanol, and raw material is easy to get, and technique is relatively uncomplicated.But its defect is also clearly, such as, with ironic hydroxide and ammonia reduction, not easily separated product, iron mud has pollution to environment; Each step reaction operability is poor, through experiment, diazotization and cyclization two step yield all very low.This method is except 40% except reporting the first step yield, does not record in other data files, and chrysophanol acetylize and oxidation obtain in the synthetic method of diacerein; see CN200410103346.0; CN200610106762.5, FR2907118, WO2008090078A1.There is expensive raw material price, the problem such as production process is loaded down with trivial details, the production cycle is long and agents useful for same toxicity is large, be not suitable for suitability for industrialized production.
And the people such as Vanessa Gonnot, Steve Tisserand are complete synthesis, mainly adopt 1-aldehyde radical benzene methyl and 1-methyl esters-3,5-bis--Ji-1-ethyl-two-ethanamide benzene to carry out reaction under cryogenic and come.After obtain product through reduction, cyclization, oxidation, hydrolysis, acetylize again.Although the method can be synthesized obtain product, reactions steps reaches 8 steps, and have employed low temperature and reach-78 DEG C, this condition is difficult to reach aborning, employ the reagent that hydrogen, palladium carbon etc. are dangerous, palladium carbon easily makes chemical reagent burn, and hydrogen is also as easy as rolling off a log burning and blast simultaneously.Working condition is difficult to reach, and cost is high, and yield is low; Be not suitable for suitability for industrialized production.
As can be seen from above complete synthesis route, there is certain difficulty in complete synthesis diacerein.Therefore domestic and international many scholars semi-syntheticly to study it; patent EP0636602 (1994) with the anthracene compounds extracted in polygonaceae natural phant for starting raw material; rhabarberone is obtained through peroxidation; in order to the hydroxyl controlled on anthraquinone ring is not oxidized; adopt the way that ethanoyl is first protected; but benzyl hydroxyl equally also generates acetic ester; when being oxidized to carboxylic acid further; the selectable scope of oxygenant is little; the oxygenant of usual employing is chromic anhydride, and needs to adopt a large amount of chromic anhydrides to be oxidized to diacerein.The method disclose from Barbaloin A after acetylize without being separated the one-step oxidation process that reoxidizes, but need the chromic anhydride oxygenant that adopts 5-10 doubly greatly excessive.Have employed the chromium oxygenant of severe toxicity, the toxicity environmental pollution of chromium oxygenant and labor protection are the difficult problems that industrialization faces, and product separation purifying is also very complicated.And (CN200610028926.7) adopts chromium reagent that rhabarberone oxidation is obtained rheum officinale aldehyde; then be diacetyl rheum officinale aldehyde with diacetyl oxide by its acidylate; again diacetyl rheum officinale formoxy-is turned to diacerein; all employ the chromium reagent that toxicity is larger, easily cause the chromium residues in environmental pollution and product.
Simultaneously patent DE2711493 (1977) the earliest discloses the semi-synthetic method preparing diacerein is use potassium bichromate to make oxygenant, disposable is carboxyl the hydroxyl direct oxidation of rhabarberone benzyl position, the intermediate product rhubarb yellow formed obtains diacerein through acetylize again, although this flow process reactions steps is less, but owing to using potassium bichromate as oxygenant, oxidizing condition is more violent, hydroxyl in the anthraquinone ring of rhubarb yellow is easy to over oxidation, reaction process is difficult to control, impurity generates more, at the bottom of reaction yield, the quality of product is also difficult to improve.
Made some to semisynthetic synthetic method in the novel method of the synthesizing diacerein such as Zhu Xing mono-, Guo Qiaofeng afterwards to change, with extract aloe rheochrysin for starting raw material by reduction, to be oxidized and diacerein is prepared in acetylize.This synthetic method avoids the oxygenant chromium trioxide used in all synthetic routes, relatively little by toxicity, the Sodium Nitrite that environmental pollution is little.But its catalyzer used is relatively costly.
Employ in patent CN101508645A with trifluoromethanesulfonic acid zinc metal reagent as catalyzer, although it is few that this synthetic method also possesses synthesis step, simple to operate, but metal catalyst adds production cost virtually, the problem of most critical is the heavy metals exceeding standard simultaneously causing end product, makes the feasibility of this synthetic method in drug manufacture not high.
Therefore, the diacetyl rhein preparation method of development of new seems particularly important.
Summary of the invention
The object of the invention is to solve the some shortcomings existed in existing diacetyl rhein preparation technology, the diacetyl rhein preparation method that a kind of technological operation is simple, yield is high, purity is high, solvent is recyclable, environmental pollution is little is provided.
In order to achieve the above object, the invention provides a kind of preparation method of diacetyl rhein, it is characterized in that, concrete steps comprise: by rhubarb yellow, catalyzer, solvent and acetylation reagent drop in reaction vessel, described catalyzer is methanesulfonic, boric acid, aluminum chloride, one or more the combination of phosphoric acid and trifluoracetic acid, described solvent is ethyl acetate, glycol dimethyl ether, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, 1, one or more combination in 4-dioxane and methyl tertiary butyl ether, temperature rising reflux reaction 6 ~ 24 hours under whipped state, after reaction terminates, reaction solution is cooled to 25 ± 5 DEG C, suction filtration, filter cake is with 1, 4-dioxane recrystallization, obtain faint yellow powdery solid diacetyl rhein.
Preferably, described catalyzer is methanesulfonic.
Preferably, the amount of substance of described catalyzer is 0.1 ~ 2 of rhubarb yellow amount of substance.
More preferably, the amount of substance of described rhubarb yellow is 1: 0.3 with the ratio of the amount of substance of catalyzer.
Preferably, in described reaction process, adopt TLC to follow the tracks of extent of reaction, detect rhubarb yellow residual content and judge reaction end.
Preferably, described solvent is ethyl acetate.
Preferably, described solvent and the weight ratio of rhubarb yellow are 1: 1 ~ 20: 1.
More preferably, described solvent and the weight ratio of rhubarb yellow are 10: 1.
Preferably, described acetylation reagent is one or both the combination in diacetyl oxide and Acetyl Chloride 98Min..
More preferably, described acetylation reagent is diacetyl oxide.
Preferably, the amount of substance of described acetylation reagent is 2 ~ 5 times of rhubarb yellow amount of substance.
More preferably, the amount of substance of described acetylation reagent is 5 times of rhubarb yellow amount of substance.
Preferably, described temperature of reaction is 85 ~ 95 DEG C.
More preferably, described temperature of reaction is 90 DEG C.
Preferably, the described reaction times is 6 ~ 24 hours.
More preferably, the described reaction times is 12 hours.
Preferably, described filtrate distillation segmentation recycling design, catalyzer and acetylation reagent, the reagent recycling of recovery.
Through a large amount of research work, the present invention finds to adopt the catalyzer that can be dissolved in reaction solvent to carry out synthesis of diacetyl rhubarb yellow.Both can avoid the residual of catalyzer, and turn avoid and aftertreatment is carried out to it.Operate quite easy, be suitable for suitability for industrialized production.
Compared with prior art, beneficial effect of the present invention is mainly reflected in:
What present invention employs that all documents and patent all do not adopt adds organic solvent to make solvent in reaction system; solve technological operation more loaded down with trivial details in existing technique; employing methanesulfonic etc. are as the catalyzer in acylation reaction simultaneously; instead of the mineral acid of organic bases or mineral alkali and some danger adopted in all technique, above 2 is key point of the present invention.Compared with existing technique, the solvent that the present invention adopts, catalyzer, acylating reagent can be recycled, and very large depth reduces production cost, and meanwhile, the present invention is not only that product yield is high, purity is high; And in product, there is no the residual of catalyzer, easy to operate, aftertreatment is simple; Solve the quality critical problem of the heavy metals exceeding standard of product simultaneously.
Comprehensive the above, the present invention has raw material and is easy to get, reagent toxicity is little, technological operation is simple, low production cost, products obtained therefrom purity and yield are all very high, and do not have the advantage such as residual of catalyzer and heavy metal in product, and this invention is the synthesis technique having fine significance in a kind of synthesis of diacetyl rhubarb yellow, be suitable for suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.In addition should be understood that those skilled in the art can make various changes or modifications the present invention, and these equivalent form of values fall within the application's appended claims limited range equally after the content of having read the present invention's instruction.
Embodiment 1
Have high input yellow acid (5g, 0.0176mmol), methanesulfonic (0.5g, 0.0052mmol), ethyl acetate 50g, diacetyl oxide (25g, 0.2451mmol) in reaction flask; 85-95 DEG C of back flow reaction 12 hours are warming up under agitation condition.After reaction terminates, suction filtration after reaction solution is cooled to 25 ± 5 DEG C, filter cake Isosorbide-5-Nitrae-dioxane recrystallization, dry, obtain slight yellow powdery solid diacetyl rhein 6.4g.HPLC purity is 99.87%, and yield is 98.76%.
Embodiment 2
Have high input yellow acid (5g, 0.0176mmol), methanesulfonic (0.5g, 0.0052mmol), DMF 50g, diacetyl oxide (25g, 0.2451mmol) in reaction flask; 85-90 DEG C of insulation back flow reaction 12 hours are warming up under agitation condition.After reaction terminates, suction filtration after reaction solution is cooled to 25 ± 5 DEG C, filter cake Isosorbide-5-Nitrae-dioxane recrystallization, dry, obtain slight yellow powdery solid diacetyl rhein 4.1g.HPLC purity is 88.62%, and yield is 63.27%.
Embodiment 3
Have high input yellow acid (5g, 0.0176mmol), methanesulfonic (0.5g, 0.0052mmol), Isosorbide-5-Nitrae-dioxane 50g, diacetyl oxide (25g, 0.2451mmol) in reaction flask; 90-95 DEG C of insulation back flow reaction 12 hours are warming up under agitation condition.After reaction terminates, suction filtration after reaction solution is cooled to 25 ± 5 DEG C, described filtrate distillation segmentation recycling design, catalyzer and acetylation reagent; the reagent recycling of reclaiming, filter cake Isosorbide-5-Nitrae-dioxane recrystallization; drying, obtains slight yellow powdery solid diacetyl rhein 6.1g.HPLC purity is 95.82%, and yield is 94.14%.
Embodiment 4
Have high input yellow acid (5g, 0.0176mmol), methanesulfonic (0.5g, 0.0052mmol), ethyl acetate 50g, diacetyl oxide (50g, 0.4902mmol) in reaction flask; 85-95 DEG C of insulation back flow reaction 12 hours are warming up under agitation condition.After reaction terminates, suction filtration after reaction solution is cooled to 25 ± 5 DEG C, described filtrate distillation segmentation recycling design, catalyzer and acetylation reagent; the reagent recycling of reclaiming, filter cake Isosorbide-5-Nitrae-dioxane recrystallization; drying, obtains slight yellow powdery solid diacetyl rhein 5.8g.HPLC purity is 99.02%, and yield is 89.51%.
Embodiment 5
Have high input yellow acid (5g, 0.0176mmol), methanesulfonic (0.5g, 0.0052mmol), ethyl acetate 50g, diacetyl oxide (25g, 0.2451mmol) in reaction flask; 86-94 DEG C of insulation back flow reaction 8 hours are warming up under agitation condition.In reaction process, adopt TLC to follow the tracks of extent of reaction, detect rhubarb yellow residual content and judge reaction end, after reaction terminates, suction filtration after reaction solution is cooled to 25 ± 5 DEG C, filter cake is with 1,4-dioxane recrystallization, dry, obtain slight yellow powdery solid diacetyl rhein 6.4g.HPLC purity is 78.62%, and yield is 98.76%.
Embodiment 6
Have high input yellow acid (5g, 0.0176mmol), methanesulfonic (0.05g, 0.0005mmol), ethyl acetate 50g, diacetyl oxide (25g, 0.2451mmol) in reaction flask; 86-92 DEG C of insulation back flow reaction 12 hours are warming up under agitation condition.After reaction terminates, suction filtration after reaction solution is cooled to 25 ± 5 DEG C, filter cake Isosorbide-5-Nitrae-dioxane recrystallization, dry, obtain slight yellow powdery solid diacetyl rhein 6.2g.HPLC purity is 43.76%, and yield is 95.68%.
Embodiment 7
Have high input yellow acid (5g, 0.0176mmol), phosphoric acid (0.5g, 0.0051mmol), ethyl acetate 50g, diacetyl oxide (25g, 0.2451mmol) in reaction flask; 85-95 DEG C of insulation back flow reaction 12 hours are warming up under agitation condition.After reaction terminates, suction filtration after reaction solution is cooled to 25 ± 5 DEG C, filter cake Isosorbide-5-Nitrae-dioxane recrystallization, dry, obtain slight yellow powdery solid diacetyl rhein 6.3g.HPLC purity is 98.54%, and yield is 97.22%.
Embodiment 8
Have high input yellow acid (5g, 0.0176mmol), boric acid (0.5g, 0.0081mmol), ethyl acetate 50g, diacetyl oxide (25g, 0.2451mmol) in reaction flask; 85-95 DEG C of insulation back flow reaction 12 hours are warming up under agitation condition.After reaction terminates, suction filtration after reaction solution is cooled to 25 ± 5 DEG C, filter cake Isosorbide-5-Nitrae-dioxane recrystallization, dry, obtain slight yellow powdery solid diacetyl rhein 5.9g.HPLC purity is 86.23%, and yield is 91.05%.
Claims (10)
1. the preparation method of a diacetyl rhein, it is characterized in that, concrete steps comprise: by rhubarb yellow, catalyzer, solvent and acetylation reagent drop in reaction vessel, described catalyzer is methanesulfonic, boric acid, aluminum chloride, one or more the combination of phosphoric acid and trifluoracetic acid, described solvent is ethyl acetate, glycol dimethyl ether, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, 1, one or more combination in 4-dioxane and methyl tertiary butyl ether, temperature rising reflux reaction 6 ~ 24 hours under whipped state, after reaction terminates, reaction solution is cooled to 25 ± 5 DEG C, suction filtration, filter cake is with 1, 4-dioxane recrystallization, obtain faint yellow powdery solid diacetyl rhein.
2. the preparation method of diacetyl rhein as claimed in claim 1, it is characterized in that, described catalyzer is methanesulfonic.
3. the preparation method of diacetyl rhein as claimed in claim 1, it is characterized in that, the amount of substance of described catalyzer is 0.1 ~ 2 of rhubarb yellow amount of substance.
4. the preparation method of diacetyl rhein as claimed in claim 1, it is characterized in that, described solvent is ethyl acetate.
5. the preparation method of diacetyl rhein as claimed in claim 1, it is characterized in that, described solvent and the weight ratio of rhubarb yellow are 1: 1 ~ 20: 1.
6. the preparation method of diacetyl rhein as claimed in claim 1, is characterized in that, described acetylation reagent is one or both the combination in diacetyl oxide and Acetyl Chloride 98Min..
7. the preparation method of diacetyl rhein as claimed in claim 1, it is characterized in that, the amount of substance of described acetylation reagent is 2 ~ 5 times of rhubarb yellow amount of substance.
8. the preparation method of diacetyl rhein as claimed in claim 1, it is characterized in that, described temperature of reaction is 85 ~ 95 DEG C.
9. the preparation method of diacetyl rhein as claimed in claim 1, it is characterized in that, the described reaction times is 6 ~ 24 hours.
10. the preparation method of diacetyl rhein as claimed in claim 1, is characterized in that, described filtrate distillation segmentation recycling design, catalyzer and acetylation reagent, the reagent recycling of recovery.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134256A (en) * | 2018-09-18 | 2019-01-04 | 江苏凯迪恩医药科技有限公司 | A kind of diacerein crystal I and the preparation method and application thereof |
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| EP0928781A1 (en) * | 1997-12-30 | 1999-07-14 | Laboratoire Medidom S.A. | Process for the preparation of rhein and its diacyl derivatives |
| CN1651394A (en) * | 2004-11-30 | 2005-08-10 | 夏士朋 | Method of preparing diacetyl parietic acid from rhubarb extract |
| CN101056839A (en) * | 2004-11-12 | 2007-10-17 | 梅迪多姆实验室股份有限公司 | Process for preparing aloe-emodin |
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| CN102408331A (en) * | 2011-10-31 | 2012-04-11 | 栗进才 | Preparation method of diacerein |
| CN102875372A (en) * | 2011-07-15 | 2013-01-16 | 台州海辰药业有限公司 | New synthesis method for diacerein |
| CN103360250A (en) * | 2012-03-30 | 2013-10-23 | 山东靶点药物研究有限公司 | High-yield diacerein synthesis method |
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2014
- 2014-09-18 CN CN201410476405.2A patent/CN104292101A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0928781A1 (en) * | 1997-12-30 | 1999-07-14 | Laboratoire Medidom S.A. | Process for the preparation of rhein and its diacyl derivatives |
| CN101056839A (en) * | 2004-11-12 | 2007-10-17 | 梅迪多姆实验室股份有限公司 | Process for preparing aloe-emodin |
| CN1651394A (en) * | 2004-11-30 | 2005-08-10 | 夏士朋 | Method of preparing diacetyl parietic acid from rhubarb extract |
| CN101209970A (en) * | 2006-12-25 | 2008-07-02 | 上海海隼化工科技有限公司 | Diethylene glycol monoacetate, diethylene glycol diacetate and preparation method thereof |
| CN102875372A (en) * | 2011-07-15 | 2013-01-16 | 台州海辰药业有限公司 | New synthesis method for diacerein |
| CN102408331A (en) * | 2011-10-31 | 2012-04-11 | 栗进才 | Preparation method of diacerein |
| CN103360250A (en) * | 2012-03-30 | 2013-10-23 | 山东靶点药物研究有限公司 | High-yield diacerein synthesis method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134256A (en) * | 2018-09-18 | 2019-01-04 | 江苏凯迪恩医药科技有限公司 | A kind of diacerein crystal I and the preparation method and application thereof |
| CN109134256B (en) * | 2018-09-18 | 2021-09-07 | 江苏德健医疗科技有限公司 | Diacerein crystal I and preparation method and application thereof |
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Application publication date: 20150121 |