CN105985242A - Preparation method of diacerein - Google Patents
Preparation method of diacerein Download PDFInfo
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- CN105985242A CN105985242A CN201510040406.7A CN201510040406A CN105985242A CN 105985242 A CN105985242 A CN 105985242A CN 201510040406 A CN201510040406 A CN 201510040406A CN 105985242 A CN105985242 A CN 105985242A
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Abstract
The invention relates to a synthetic route and a preparation method of diacerein (I). The preparation method includes the steps of: (A) synthesizing a compound (1) from 1-chloro-2,5-dimethoxybenzene; (B) performing a condensation reaction to 2,5-dimethoxy-4-chlorobenzaldehyde and diethyl succinate as raw materials to obtain a compound (3); (C) cyclizing the compound (3) to obtain a compound (4), and deprotecting and oxidizing the compound (4) to obtain a compound (5); (D) hydrolyzing and cyclizing the compound (5) to prepare a compound (7); and (E) deprotecting, hydrolyzing and esterifying the compound (7) to obtain the target compound diacerein. The preparation method is simple in operations and employs easy-to-control reactions and easy-to-obtain raw materials. The product is easy to separate. The method avoids usage of a chromium oxidant and solves a problem of residue of chromium, is low in cost and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of medicament for treating arthritis diacerein variation route and preparation method, belong to technical field of medicament.
Background technology
Diacerein is a kind of new interleukin-11 β (1L-1 β) inhibitor, is mainly used in clinically treating osteoarthritis and drawing property arthritis late.Research in recent years finds, it has good curative effect to rheumatoid arthritis, osteoporosis, adult acute's breathing syndrome and emphysema.The diacerein synthetic route of report mainly has two kinds at present: complete synthesizing process and semi-synthesis method.
Complete synthesizing process is mainly with 3-nitrophthalic acid acid anhydride as initiation material; Friedel-Crafts reaction is carried out with metacresol; again through reduction, cyclization and diazonium compound intermediate chrysophanol, then chrysophanol acetylation and oxidation are obtained diacetyl rheum emodin (CN200410103346.0；CN200610106762.5；CN200410103346.0).
The method exists that expensive raw material price, generation process be loaded down with trivial details, production cycle length and the problem such as agents useful for same toxicity is big, is poorly suited for industrialized production.Gemma in 1998 et al. (EP0822177A1), with 2,3-dimethylanisole and gavaculine are raw material, diacerein have been synthesized through ten steps.This synthetic route is long, and raw materials consumption is big, and relates to the problem such as selective esterification, amino group.Vanessa Gonnot in 2007 et al. (Tetrahedron Letters 48
(2007) 7,117 7119) it is raw material with the substituted N of o-methoxybenzaldehyde and alkoxyl, N-diethylbenzene diformamide, first under the effect of butyl lithium, in-78oThere is ring closure reaction under C, then carry out hydro-reduction open loop, then through the step synthesizing diacerein such as cyclization, oxidation.This synthetic route to use expensive butyl lithium raw material, and-78oC reacts, and is awkward.
The semi-chemical synthesis of diacerein be the anthraquinone analog compound extracted in some natural plants as initiation material, then obtain diacerein through a series of chemical reaction.As: first with acetic anhydride by acylated for the barbaloin acetylation barbaloin that obtains, then with chromium reagent, acetylation barbaloin is oxidized to diacetyl rhein (EP0636602).Or use chromium reagent that aloin is oxidized to Radix Et Rhizoma Rhei aldehyde, then be acylated as diacetyl Radix Et Rhizoma Rhei aldehyde with acetic anhydride, then diacetyl Radix Et Rhizoma Rhei formoxy-is turned to diacetyl rhein (CN200610028926.7).
Both approaches all employ the chromium reagent that toxicity is bigger, easily causes the chromium residues in environmental pollution and product.
Another semi-synthesis method is to use juglone method (Tetrahedron. 1984,40 (22) 4751；Liebigs Ann. Chem.1981,
2285): 1) chrysophanol, yield 49.6% are prepared with juglone and 6-methoxyl group-4-methyl-2H-pyran-2-one through three-step reaction.But the method uses Azimethylene. when preparing pyranone intermediate, operates dangerous；The most again with 48% hydrobromic acid demethylation, this method is not suitable for industrialized production.2) carry out D-A reaction and Jone ' s reagent oxidation with juglone and isoprene trimethylsilyl ethers, then aromatisation obtains chrysophanol, yield 45.8%.Isomer is there is during this method cyclization, isolated and purified difficult.
Halo quinone method is also a kind of method (US3773801 of synthesis Radix Et Rhizoma Rhei compounds；US5948924): 1) the bromo-5 chloro-8-hydroxyquinone of 2-and 1 are used, 1-diethoxy-3-dimethyl butadiene carries out D-A reaction, and reaction generates ethoxy compound and takes off ethyl through hydroiodic acid, then obtains chrysophanol with chromic acid oxidation, but hydroiodic acid is expensive, seriously polluted to human and environment.2) with 3-chlorine juglone and 1-acetoxy-3-methyl isophthalic acid, 3-butadiene is raw material, obtains product by D-A reaction and aromatisation, but has isomeric by-products during cyclization.
Summary of the invention
For the problems referred to above, the present invention provides the preparation method of a kind of new diacerein, this prepare raw material be easy to get, easily operated, avoid chromium residues.
The synthetic route of the present invention is as follows:
The synthesis of compound 2 uses 1-chloro-2, and 5-dimethoxy benzene is initiation material, reacts with hexamethylenetetramine in the presence of trifluoroacetic acid, obtains after alkali carbonate regulation PH, and yield is up to 87%.
The synthesis of compound 3 uses sodium hydride or calcium hydride to be alkali, is condensed with diethyl succinate in the presence of the absolute ethanol of catalytic amount, uses TLC to follow the tracks of reaction.
The synthesis of compound 4 is to be condensed to yield with acetic anhydride in the presence of sodium acetate or potassium acetate.
The synthesis of compound 5 uses ammonium ceric nitrate as oxidant, and with acetonitrile as solvent, yield reaches 81%.
Compound 6 uses two kinds of different synthetic methods synthesis.
Compound 7 is obtained in the case of triethylamine exists by D-A reaction.
The building-up process of compound 8 can use lewis acid or Protic Acid Catalyzed.
With 1-chloro-2,5-dimethoxy benzene is initiation material, diacerein is synthesized through nine steps, and its advantage is embodied in the following aspects: the raw material used is all common raw material, is not directed to special reagent；Whole process route is not involved with the specific responses such as high temperature, high pressure, low temperature, operating aspect, it is simple to realize industrialization；It is not directed to chromium reagent, it is to avoid environmental pollution；This process route belongs to complete synthesis route, and raw material sources are extensive.
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited to this:
Embodiment one, the synthesis of compound 1
450 milliliters of (5.84mol) trifluoroacetic acids are joined 1-chloro-2, in the mixed system of 5-dimethoxy benzene (51.8 grams, 300mmol) and hexamethylenetetramine (42 grams, 300mmol), this system is immediately placed in and is preheating to (80-90 DEG C), refluxes 12 hours.Reflux complete, pour in 600 grams of trash ices while hot, darkorange mixture quickly stirs 30 minutes, after ice dissolves, add Excess solid carbonic acid hydrogen sodium and make system be alkalescence, until producing yellow mercury oxide, add 300 milliliters of water stirrings until solidifying, gained solid is through sucking filtration, 500 milliliters of washings, and yellow solid dries, and obtains compound 1 with high boiling petroleum ether recrystallization.Fusing point: 106 DEG C, Rf=0.45(chloroform/hexane=3:1).Yield 87%.
Embodiment two, the synthesis of compound 3
By sodium hydride (24.0 grams, 1.04mol, by 40 gram of 60% scattered sodium hydride of mineral oil, washed twice by hexane, toluene is washed and is once obtained.) join in reaction bulb, add 500 milliliters of toluene, stirring, the lower absolute ethanol (0.5 milliliter) adding catalytic amount of nitrogen protection, dropping diethyl succinate (290 grams, 1.2mol) and 1(0.42mol), the rate of addition of succinate has been maintained at hydrogen and has stably released and temperature is less than 55 DEG C, drip and finish, mixture stirs 1 hour at room temperature, it is subsequently adding 145 milliliters of (1.74mol) concentrated hydrochloric acid and 200 milliliters of water, organic layer is with the solution of potassium carbonate (500 milliliters of 1M, 0.5mol) wash, water layer is with concentrated hydrochloric acid (146 milliliters, 1.74mol) acidifying, yellow oil extracts with ether, anhydrous magnesium sulfate is dried, grease is obtained after solvent is evaporated off, solid 3 is obtained after recrystallization.Fusing point: 110 DEG C, Rf=0.62, toluene: acetic acid: methanol=120:18:1).Yield 91%
Embodiment three, the synthesis of compound 4
By thick 3(0.24mol) join in reaction bulb, add acetic anhydride (124 grams, 1.21mol) and anhydrous sodium acetate (36.1 grams, 0.44mol), the lower backflow of nitrogen protection 3 hours.Mixture is cooled to room temperature, and sodium acetate crystallizes twice, second day, mixture is poured in 500 grams of ice, is stirred vigorously, until there being orange-brown spongy solid to produce, solid washes with water repeatedly, to remove acetic acid, is dissolved in ether by solid, anhydrous magnesium sulfate is dried, filter, ether is evaporated off, obtains brown solid, then use a small amount of methanol extraction, filter immediately.Rf=0.84 (3:l chloroform/methanol).Yield 83%.
Embodiment four, the synthesis of compound 5
Join 4 in reaction bulb, add acetonitrile 100 milliliters, it is stirred vigorously, in 5 minutes, is dividedly in some parts 20 milliliters of aqueous solutions of ammonium ceric nitrate (3.58 grams, 6.53mmol), the transition state being become black by green can be observed after adding every time, mixed system stirs 1 hour at room temperature, then dilutes with 800 milliliters of water, and ether extracts, anhydrous magnesium sulfate is dried, and solvent is evaporated off and obtains yellow solid 5.Rf=0.84 (3/1 chloroform/hexane).Yield 81%
Embodiment five, the synthesis of compound 6
Method one: by 5(1.01mmol) join in reaction bulb, add 30 milliliters of acetone and 13.5 milliliters of (40.5mmol) 3M hydrochloric acid, it is stirred at reflux 0.5 hour, add another part of 3M hydrochloric acid 13.5 milliliters (40.5mmol) and join in reaction system, continue backflow 2 hours, after being cooled with ice, then extract with ether (2 × 50mL), ether layer washing (5 × 100mL)
Method two: by 5(4.0mmol) join in reaction bulb; add 20 milliliters of dichloromethane; under nitrogen protection; add ammonium chloride (5.33 grams, 40mmol) at room temperature, continue stirring 1 hour; 50 milliliters of water and 5 milliliters of concentrated hydrochloric acid are added in 0 DEG C; extracting with dichloromethane (2 × 50mL), organic layer is dried with anhydrous magnesium sulfate, solvent is evaporated off and obtains orange product 6. Rf=
0.48 (3/1 chloroform/hexane).
Embodiment six, the synthesis of compound 7
By 6(0.1 gram, 0.36mmol) join in reaction bulb, add 1-methoxycyclohexyl diene (0.091 g, 0.54 mmol; 65%
Tech), Et3N (0.040 g,
0.39 mmol) and 25 milliliters of dichloromethane, stirring 24 hours, are evaporated off solvent at room temperature, and green oil thing heats in the oil bath be preheating to 140 DEG C, oil solidified after a few minutes, obtains dark brown solid, with recrystallizing methanol, mp=211-212oC;
Rf=0.26 (3:l chloroform/hexane).
Embodiment seven, the synthesis of compound 8
7 (0.067 g, 0.205 mmol) are joined in reaction bulb, adds 15 milliliters of dichloromethane, be stirred vigorously, add AlCl3 (0.547 g,
4.1 mmol), mixed system stirs 24 hours at room temperature, is carefully added into 15 milliliters of water and 1 milliliter of concentrated hydrochloric acid, extracts with ether (3 × 50mL), solvent is evaporated off and obtains yellow solid powder 8.mp = 162-164oC。Rf=0.54 (3:l chloroform/hexane).
Embodiment eight, the synthesis of compound 9
8 0.37mmol are joined in reaction bulb, adds sodium hydroxide (12.5mmol) solution of 5 milliliter 10%, under nitrogen protection, stirring 24 hours at room temperature, add 0.5 milliliter of concentrated hydrochloric acid under ice bath, ether extracts, solvent is evaporated off and obtains 9.m.p = 320-323oC;
Rf=0.60 (3:1 chloroform/hexane).
Embodiment nine, the synthesis of compound 10
Joining in reaction bulb by 3mmol 9, add the potassium hydroxide solution of 1.4 milliliters of 6.4N, lower addition 3 gram ice are stirred at room temperature, add 0.71 milliliter of acetic anhydride, stir 45 minutes, add 25 milliliters of water, stir 30 minutes under ice bath, sucking filtration obtains yellow solid 10.
Claims (6)
1. the diacerein preparation method described in claim 1, it is characterised in that the raw material that the synthesis of compound 2 is used is common industrial chemicals, and reaction temperature is at 60-100 DEG C, the alkali used can be inorganic base or organic base, such as: alkali-metal carbonate, pyridine, piperidines, nafoxidine；It is characterized in that the alkali that second step condensation reaction is used can be sodium hydride, calcium hydride；
Product, without purification, can be directly used for next step reaction.
2. the diacerein preparation method described in claim 1, it is characterised in that the carboxylate that the synthesis of compound 4 uses can be sodium acetate, potassium acetate；Reaction need to be reacted under inert gas shielding.
3. the diacerein preparation method described in claim 1, it is characterised in that the building-up process of compound 5 have employed ammonium ceric nitrate, and solvent can use acetonitrile or acetone.
4. the diacerein preparation method described in claim 1, it is characterised in that the synthesis of compound 6 have employed two kinds of different methods.
5. the diacerein preparation method described in claim 1, it is characterised in that the triethylamine employed in the synthesis of compound 7 can replace with alkali-metal carbonate, pyridine, piperidines.
6. the diacerein preparation method described in claim 1, it is characterised in that the aluminum chloride employed in the synthesis of compound 8 can replace, such as boron trifluoride, sulphuric acid, phosphoric acid with other lewis acids or Bronsted acid；The amount of aluminum chloride is 2-25 times of raw material dosage molal quantity.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110790657A (en) * | 2019-10-22 | 2020-02-14 | 上海交通大学 | Synthesis method of 7-methyl juglone |
Citations (3)
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|---|---|---|---|---|
| CN1088907A (en) * | 1993-01-02 | 1994-07-06 | 马道斯有限公司 | The preparation method of diacetyl rhein |
| US5391775A (en) * | 1991-06-25 | 1995-02-21 | Madaus Ag | Process for production of diacetylrhein |
| CN103965062A (en) * | 2013-01-29 | 2014-08-06 | 上海源力生物技术有限公司 | Water-soluble choline salts of rhein and rhein derivative, preparation method and application of choline salts in medicine |
-
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- 2015-01-27 CN CN201510040406.7A patent/CN105985242A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5391775A (en) * | 1991-06-25 | 1995-02-21 | Madaus Ag | Process for production of diacetylrhein |
| CN1088907A (en) * | 1993-01-02 | 1994-07-06 | 马道斯有限公司 | The preparation method of diacetyl rhein |
| CN103965062A (en) * | 2013-01-29 | 2014-08-06 | 上海源力生物技术有限公司 | Water-soluble choline salts of rhein and rhein derivative, preparation method and application of choline salts in medicine |
Non-Patent Citations (1)
| Title |
|---|
| JAMES L. BLOOMER等: "Preparation of functionalized juglone acetates and juglones via 1,4-dimethoxynaphthalene derivatives: synthesis of anthraquinones related to rhein and aloe-emodin", 《J.ORG.CHEM.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110790657A (en) * | 2019-10-22 | 2020-02-14 | 上海交通大学 | Synthesis method of 7-methyl juglone |
| CN110790657B (en) * | 2019-10-22 | 2021-06-08 | 上海交通大学 | Synthesis method of 7-methyl juglone |
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Application publication date: 20161005 |