CN102887907A - New process for preparing beta-arteether by single reaction kettle method by taking artemisinin as raw material - Google Patents

Abstract

The invention provides a method for semi-synthesizing beta-arteether by a single reaction kettle method by taking artemisinin as a raw material. In absolute ethyl alcohol or a moderate polarity ether solvent system such as tetrahydrofuran, borohydride such as potassium borohydride and the like is taken as a reducing agent to reduce artemisinin so as to obtain dihydroartemisinin. Without separation or purification, methanesulfonic acid, phosphoric acid or the like is added to adjust the pH value to neutral, and then, a catalyst such as Lewis acid ZnBr2 and the like is continuously added to react to prepare arteether. After reaction, separation and purification are directly carried out by way of extraction, crystallization and recrystallization to obtain beta-arteether with high yield (0.85k of beta-arteether is prepared from 1kg of artemisinin), wherein the content of beta-arteether is more than 99.0%; the content of the related substance alpha-arteether is less than 0.2%; the content of dihydroartemisinin is less than 0.1%; and the content of the total impurities is less than 0.5% of the quality product. The method has the advantages of simple process flow, low equipment requirement, convenience in operation, high atom economy, low carbon and environment friendliness, and is very suitable for industrial production.

Description

The novel process for preparing β-arteether take Artemisinin as the raw material single reaction still method

Technical field

The present invention relates to a kind of artemisinin derivative special efficacy anti-malaria medicaments-β-arteether, be specifically related to prepare as the raw material single reaction still method take Artemisinin the novel process of arteether.

Background technology

Artemisinin is that China scientist in 1971 separates a kind of sesquiterpene lactones compound that obtains from feverfew Herba Artemisiae annuae (wormwood artemisia of also grieving, smelly wormwood artemisia) leaf extracting section, and the peroxide bridge that characteristics are arranged in the Artemisinin structure most is the crucial group of its performance drug activity.Sweet wormwood (Herba Artemisiae annuae) or its extract are used for treating the relevant disease of malaria more than 2,000 year history, compare with Artemisinin, Artemisinin series derivates such as dihydroarteannuin, Artemether, arteether and Artesunate, show better antimalarial effect, replace later on chloroquine, PIPERAQUINE, quinine etc. in 2000, and become the antimalarial agent of World Health Organization's first-selection.Be the present medicine of the most effective treatment encephalic malaria and anti-Chloroquine-resistant Falciparum Malaria disease in the world, be called " maximum for the treatment of malaria is wished " by the World Health Organization, have fast, efficient, without the feature of resistance, low toxic side effect.Nearly 30 years studies show that, Artemisinin and derivative thereof also have anti-pregnant, schistosomicide, anti-fibrosis, resisting toxoplasmosis, anti-inflammatory and inhibition tumor cell propagation isoreactivity.

In artemisinin derivative series, ether derivative Artemether and arteether that Artemisinin is reduced into behind the dihydroarteannuin are that antimalarial active is preferably with the most stable.Especially Artemether, its effect is better than arteether, develop more early, is the most salable artemisinin derivative at present, accounts for more than 50% of the derivative market share.Comparatively speaking, although arteether is active in Artemether, increases a little dosage and can reach the Artemether in Treatment effect fully; It is fat-soluble, the transformation period all is better than Artemether, in the body Artemether and arteether respectively metabolism be dihydroarteannuin+methyl alcohol or ethanol, arteether is better than having the Artemether of methyl alcohol metabolite aspect toxic side effect.So along with the mining inetesity to arteether strengthens, doctor and patient strengthen the approval of arteether, arteether will brought into play very huge effect aspect the anti-plasmodium disease.

What the arteether syntheti c route had been reported has following several:

Route one is present arteether suitability for industrialized production main technique, and directly take Artemisinin as raw material, with sodium borohydride reduction, separation and purification obtains into dihydroarteannuin in methanol solution, again in ethanolic soln with tosic acid, BF₃/ ether, AlCl₃, the catalyst etherifying such as trimethylchlorosilane and storng-acid cation exchange resin gets arteether, α-arteether and β-arteether overall yield between 40%～75%, configuration α: β (Pu, Y.M. between 1: 4～1: 1; Ziffer, H.; Diastereofacial additions to a beta-substituted glycal, anhydrodihydroartemisinin.Heterocycles 1994,39,2,649.Bhakuni, R.S.; Jain, D.C.; Sharma, R.P.; An improved procedure for the synthesis of ethers of dihydroartemisinin.Indian J Chem 1995,34B, 6,529.El-Feraly, F.S.; Al-Yahya, M.A.; Orabi, K.Y.; McPhail, D.R.; McPhail, A.T.; A new method for the preparation of arteether and its C-9epimer.J Nat Prod 1992,55,7,878.Singh, C.; Tiwari, P.; A one-pot conversion of artemisinin to its ether derivatives.Tetrahedron Lett 2002,43,40,7235.Lin, A.J.; Klayman, D.L.; Milhous, W.K. (Department of the Army); Novel antimalarial dihydroartemisinin derivs..US 4791135.Brossi, A.; Venugopalan, B.; Gerpe, L.G.; Yeh, H.J.C.; Flippen-Anderson, J.L.; Buchs, P.; Luo, X.D.; Milhous, W.; Peters, W.; Arteether, a new antimalarial drug:Synthesis and antimalarial properties.J Med Chem 1988,31,3,645.Kumar, S.; Jain, D.C.; Bhakuni, R.S.; Saxena, S.; Vishwakarma, R.A. (Council of Scientific and Industrial Research); Preparation of arteethers.GB 2360517.).Route one reaction formula is seen Fig. 1.

The first step of route two is identical with above-mentioned technique, gets dihydroarteannuin with the sodium borohydride reduction Artemisinin first, then in dichloromethane solution, obtains 9 (10)-alkene-Artemisinin with the Vanadium Pentoxide in FLAKES dehydration.Again in ethanolic soln with PPh₃/ HBr catalysis addition 9 (10)-alkene-Artemisinin obtains 9 α, 10 β-arteether and 9 β, 10 β-arteether (9 β, 10 β-arteether is β-arteether) mixture (Pu, Y.-M.; Ziffer, H.; Synthesis of11-[3H]-arteether, an experimental antimalarial drug.J Label Compd Radiopharm 1993,33,11,1013.Kumar, S.; Jain, D.C.; Bhakuni, R.S.; Saxena, S.; Vishwakarma, R.A. (Council of Scientific and Industrial Research); Process for the preparation of arteethers from dihydroartemisinin.US 6346631.).Route two reaction formula are seen Fig. 2.

But there are following shortcomings in above arteether preparation method:

(1) at present take Artemisinin as raw material, process is reduced into dihydroarteannuin, the technique of resynthesis arteether, and productive rate is too low, and maximum output is calculated with β-arteether and is no more than 60%;

(2) reaction is incomplete, and raw material has residual, and by product α-arteether accounting example is large, affects separation and the purifying of β-arteether finished product, and critical impurities α-arteether is difficult to control;

(3) from the Artemisinin initial calculation, technical process is relatively many, complicated operation, and equipment investment is larger;

(4) Atom economy is low, and the chemical feedstocks usage quantity is large, and by product and effluent discharge are many, and energy consumption consumption is large, and technique environmental protection control difficulty is large.

Because above shortcoming, present β both domestic and external-arteether production cost is high, and quality product is difficult to control, so that the application quantity of β-arteether is always very little, compares the less than 5% antimalarial market share with Artemether and Artesunate.For overcoming above-mentioned technique shortcoming, reduce β-arteether production cost, improving β-arteether productive rate and quality is purpose, the feature part that the present invention is different from aforesaid method is:

(1) the present invention adopts single reaction still method, saves the loaded down with trivial details intermediate treatment links of process such as separation, purifying, concentrated, extraction, column chromatography and makes simple to operately, and can strictly control institute and with an organic solvent reclaim;

(2) directly take Artemisinin as raw material, adopt the relatively low homogeneous phase reduction agent of price, such as lithium borohydride, zinc borohydride, POTASSIUM BOROHYDRIDE etc.Solvent uses dehydrated alcohol or cyclic ethers class Semi-polarity solvent such as tetrahydrofuran (THF), 1,3-dioxane and Isosorbide-5-Nitrae-dioxane etc.;

(3) step (2) gained dihydroarteannuin solution is neutralized to pH value 7 without purification process with organic or mineral acid, and the reaction solution after the neutralization adds Lewis acid catalyst for etherification such as SnCl again₂, CaCl₂, FeCl₃, ZnI₂, ZnBr₂, SbCl₃, (Ph3P)₃RhCl etc. react with dehydrated alcohol;

(4) step (3) gained arteether reaction soln is through concentrating under reduced pressure, again with organic solvent such as ethyl acetate, ethylene dichloride, methylene dichloride, sherwood oil etc. and pure water extracting and separating;

(5) collect organic phase, drying, condensing crystal and recrystallization obtain β-arteether elaboration, and productive rate is that the 1kg Artemisinin can get β-arteether 0.85kg.

Compare with reporting the arteether technology of preparing, the technology of the present invention has that technique is simpler, cost is cheaper, the advantage of better quality.

Summary of the invention

The key problem that the present invention need to solve is to improve take the productive rate of Artemisinin as the semi-synthetic synthetic arteether of raw material, and especially the ratio of chiral isomer α-arteether and β-arteether has comparative advantage the better β-arteether of drug activity.Adopt suitable equipment and process, can reach easy and simple to handle, be easy to health maintenance, greatly reduce the production cost of β-arteether simultaneously.Concrete steps are as follows:

1, Artemisinin is placed the stainless steel cauldron of jacketed, stirring, the dehydrated alcohol or the Semi-polarity cyclic ethers kind solvent that under-5～25 ℃ of conditions, add 10～20 times of volumes of Artemisinin quality, such as tetrahydrofuran (THF) or 1,3-dioxane or Isosorbide-5-Nitrae-dioxane Artemisinin is separated fully;

2, stir on the limit, homogeneous phase reduction agent POTASSIUM BOROHYDRIDE or zinc borohydride or the lithium borohydride of 0.5～1.0 times of Artemisinin quality dropped on the limit in batches, and it is complete to feed intake in 30～90min, and temperature control is in-5 ℃～25 ℃, thin-layer chromatography monitoring Artemisinin complete reaction can be considered reduction reaction and finishes;

3, with about a kind of accent reacting liquid pH value to 7 in organic acid such as methylsulfonic acid, tosic acid or mineral acid phosphoric acid, the vitriol oil etc.;

4, continue dropping into catalyst for etherification in the room temperature downhill reaction liquid is 0.1～0.5 times of Artemisinin quality, and dropping into dehydrated alcohol is 10～30 times of volumes of Artemisinin quality, and temperature control reacts 1～3h between 5 ℃～55 ℃;

5, thin-layer chromatography monitoring dihydroarteannuin complete reaction, temperature control is evaporated to out solvent-free between 45 ℃～55 ℃, the ethyl acetate or methylene dichloride or ethylene dichloride or the sherwood oil that add 10～15 times of volumes of Artemisinin quality, and add the pure water of two times of solvent volume, stir extraction 15min, separatory, with equivalent organic solvent re-extract once;

6, merge organic phase, take 5% sodium hydrogen carbonate solution volume as organic phase 1/2 extracting and washing, wash organic phase to neutral with pure water again, tell organic phase with anhydrous sodium sulfate drying, the concentrating under reduced pressure crystallization, again with ethyl acetate or acetone or ethanol or sherwood oil recrystallization, obtain content greater than 99.0% β-arteether elaboration.

The present invention adopts single reaction still method directly by the semi-synthetic β-arteether of Artemisinin, reduces pilot process, greatly reduces the use of organic solvent, reclaims simultaneously as far as possible and uses solvent, thereby reduce the pollutent possible to environment.β-arteether productivity ratio bibliographical information technique is higher, greatly improves chemical Atom economy, reduces energy consumption, and low-carbon (LC), efficient is suitable for industrialized production.

Description of drawings:

Fig. 1 is route one arteether building-up reactions formula

Fig. 2 is route two arteether building-up reactions formulas

Embodiment:

Further illustrate in the following embodiments the present invention, this does not limit the scope of the invention.

Embodiment 1

Take by weighing Artemisinin 5.0kg in the jacketed stainless steel cauldron, add dehydrated alcohol 80.0L, the stirring at room dissolving.Temperature is 0 ℃ in the freezing plant control stainless steel cauldron, adds zinc borohydride 3.5kg in 30min in batches, and temperature control is in reacting 30min below 5 ℃ again, and thin layer is monitored to Artemisinin raw material point and disappeared.The control reactor temperature stops reduction reaction about adding methylsulfonic acid or tosic acid adjust pH to 7 below 10 ℃.Continue to drop into the anhydrous ZnI of 0.70kg₂The perhaps anhydrous ZnBr of 0.50kg₂, temperature control is in 45 ℃ of reaction 2h, and thin layer is monitored to dihydroarteannuin point and is disappeared.Temperature control is in 55 ℃, is evaporated to solvent-freely to go out, and adds ethyl acetate 50L and pure water 100L, stirs extraction 15min.Tell organic phase, with ethyl acetate 75L extraction once, merge organic phase again.Organic phase with 5% sodium hydrogen carbonate solution 50L back extraction once, then is washed till neutrality with pure water again, tells organic phase with anhydrous sodium sulfate drying, and again concentrating under reduced pressure crystallization obtains the arteether crude product.With 25L ethanol thermosol and suitably concentrated, recrystallization obtains β-arteether elaboration 0.85kg with crude product, and the HPLC detection level is greater than 99.0%, and related substances α-arteether is less than 0.2%, and dihydroarteannuin is less than 0.1%, and total impurities is less than 0.5%.

Embodiment 2

Take by weighing Artemisinin 5.0kg in the jacketed stainless steel cauldron, add tetrahydrofuran (THF) 50.0L, the stirring at room dissolving.Temperature is 0 ℃ in the freezing plant control stainless steel cauldron, adds POTASSIUM BOROHYDRIDE 3.0kg in 60min in batches, and temperature control is in reacting 60min below 15 ℃ again, and thin layer is monitored to Artemisinin raw material point and disappeared.Control reactor temperature below 10 ℃ adds phosphoric acid or to stopping reduction reaction about vitriol oil adjust pH to 7.Continue to drop into dehydrated alcohol 10L and the anhydrous SnCl of 0.60kg₂, CaCl₂, FeCl₃Perhaps SbCl₃, temperature control is in 55 ℃ of reaction 3h, and thin layer is monitored to dihydroarteannuin point and is disappeared.Temperature control is in 45 ℃, is evaporated to solvent-freely to go out, and adds ethylene dichloride 50L and pure water 100L, stirs extraction 15min.Tell organic phase, with ethylene dichloride 50L extraction once, merge organic phase again.Organic phase with 5% sodium hydrogen carbonate solution 50L back extraction once, then is washed till neutrality with pure water again, tells organic phase with anhydrous sodium sulfate drying, and again concentrating under reduced pressure crystallization obtains the arteether crude product.With 20L acetone thermosol and suitably concentrated, recrystallization obtains β-arteether elaboration 0.83kg with crude product, and the HPLC detection level is greater than 99.0%, and related substances α-arteether is less than 0.2%, and dihydroarteannuin is less than 0.1%, and total impurities is less than 0.5%.

Embodiment 3

Take by weighing Artemisinin 5.0kg in the jacketed stainless steel cauldron, add 1,3-dioxane 60.0L, the stirring at room dissolving.Temperature is 0 ℃ in the freezing plant control stainless steel cauldron, adds lithium borohydride 2.5kg in 40min in batches, and temperature control is in reacting 50min below 20 ℃ again, and thin layer is monitored to Artemisinin raw material point and disappeared.The control reactor temperature stops reduction reaction about adding phosphoric acid or vitriol oil adjust pH to 7 below 10 ℃.Continue to drop into dehydrated alcohol 10L and 0.50kg anhydrous (Ph3P)₃RhCl, temperature control is in 15 ℃ of reaction 2h, and thin layer is monitored to dihydroarteannuin and is put 1 ‰ dihydroarteannuin standard substance points.Temperature control is in 45 ℃, is evaporated to solvent-freely to go out, and adds dichloromethane 50L and pure water 100L, stirs extraction 15min.Tell organic phase, with methylene dichloride 50L extraction once, merge organic phase again.Organic phase with 5% sodium hydrogen carbonate solution 50L back extraction once, then is washed till neutrality with pure water again, tells organic phase with anhydrous sodium sulfate drying, and again concentrating under reduced pressure crystallization obtains the arteether crude product.With 20L ethyl acetate thermosol and suitably concentrated, recrystallization obtains β-arteether elaboration 0.81kg with crude product, and the HPLC detection level is greater than 99.0%, and related substances α-arteether is less than 0.1%, and dihydroarteannuin is less than 0.1%, and total impurities is less than 0.3%.

Claims (10)

1. a method for preparing the intermediate double hydrogen arteannuin of arteether is characterized by, and adds homogeneous phase reduction agent POTASSIUM BOROHYDRIDE (perhaps lithium borohydride, zinc borohydride) in the ethanol solution of Artemisinin in batches.

2. require described method according to right 1, it is characterized in that reductive agent is that the consumption of hydroborate is 0.5～1.0 times of Artemisinin quality, the dehydrated alcohol consumption is 10～20 times of volumes of Artemisinin quality.

3. require described method according to right 1,2, it is characterized in that adding reductive agent control temperature at-5 ℃～25 ℃, temperature of reaction is at 0 ℃～25 ℃, reaction times 1～2h.

4. according to right 1,2,3 require described method, and reduction reaction is finished directly with about a kind of accent reacting liquid pH value to 7 in methylsulfonic acid, tosic acid or mineral acid phosphoric acid, the sulfuric acid etc.

5. according to right 1,2,3,4 require described method, it is characterized in that continuing to add lewis acid catalyst such as SnCl in the system that contains the intermediate double hydrogen arteannuin₂, CaCl₂, FeCl₃, ZnI₂, ZnBr₂, SbCl₃, (Ph3P)₃RhCl etc.

6. require described method according to right 5, it is characterized in that the Lewis acid consumption is 0.1～0.5 times of Artemisinin quality.

7. require described method according to right 6, it is characterized in that temperature control reacts 1～3h between 5 ℃～55 ℃, reaction is finished, and temperature control is evaporated to solvent-free between 45 ℃～55 ℃, must react cream dress thing.

8. require described method according to right 7, it is characterized in that adding to cream dress thing ethyl acetate or methylene dichloride or ethylene dichloride or the sherwood oil of 10～15 times of volumes of Artemisinin quality, and adding the pure water of two times of solvent volume, the solvent extraction secondary merges organic phase.

9. require described method according to right 8, it is characterized in that organic phase strips with 5% sodium bicarbonate, with pure water organic phase is washed till neutrality again.

10. require described method according to right 8, it is characterized in that organic phase with anhydrous sodium sulfate drying, the concentrating under reduced pressure crystallization again with ethyl acetate or acetone or ethyl alcohol recrystallization, obtains content greater than 99.0% β-arteether elaboration 0.85kg.

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