CN102351875A - Method for recycling mother solution generated in process of producing artemether - Google Patents
Method for recycling mother solution generated in process of producing artemether Download PDFInfo
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Abstract
The invention provides a method for recycling mother solution generated in the process of producing artemether. In the conventional method for recycling alpha-artemether, the integral utilization rate of unit artemisinin and the total yield of beta-artemether are low. The method comprises the following steps of: evaporating artemether mother solution generated in the process of producing the artemether to remove methanol, performing concentration pretreatment, extracting by using a solvent, converting part of alpha-artemether and dihydroartemisinin into the beta-artemether in the presence of acid serving as a catalyst, neutralizing, washing, concentrating, and recrystallizing in a methanol-water system to generate the beta-artemether with high purity. The process is simple and high in recycling value and can be used for industrial production.
Description
Technical field
The present invention relates to chemical pharmacy field, the recoverying and utilizing method of the mother liquor that is produced in specifically a kind of Artemether production process.
Background technology
Artemisinin is China pharmacy worker a kind of sesquiterpene lactones compounds with peroxide bridge structure that extraction separation obtained from feverfew chrysanthemum mugwort in 1971, and it is a kind of new antimalarial agent that China succeeds in developing in the world first.On the basis of Artemisinin, through structure of modification, derivatives such as the Artemether of getting back, arteether, Artesunate.The antimalarial active of Artemether is 6 times of Artemisinin.
Artemether obtains dihydroarteannuin through reduction earlier by Artemisinin, obtains through methyl-etherified again.And Artemisinin generally extracts from Herba Artemisiae annuae and obtains, and contains 0.7% the Artemisinin of having an appointment in the general Herba Artemisiae annuae, and content is very low.Artemether has α-Artemether and two kinds of epimers of β-Artemether, and what use in the medicine is β-Artemether.Being that solvent carries out methyl-etherified when reaction with the methylene dichloride, generate the β-Artemether and α-Artemether of 10-15% of 76-78%, pass through crystallization, α-Artemether of 50% and β-Artemether of 12-18% are arranged in the mother liquor approximately.The yield of methyl-etherified is about 75%, and is relatively low.
Artemether (Artemether), chemical being called (3R, 5aS, 6R, 8aS, 9R, 10S, 12R, 12aR)-and decahydro-10-methoxyl group-3,6,9-trimethylammonium-3,12-bridging oxygen-12H-pyrans is [4,3-j]-1 also, and 2-benzo two plugs are flat, and structural formula is following:
The report of recycling α-Artemether is less relatively, mainly contains the methods involving that two patent documentations have been reported recycling α-Artemether at present.Wherein, patent documentation EP0330520 relates to α-arteether epimerization is turned to the technology of β-arteether, and crystallization yield is 30%-40%, and yield is lower.Patent documentation CN1106011A then is converted into dihydroarteannuin with α-Artemether; Yield is 53%-56%; But repeat the experiment of this patent documentation; Do not obtain the dihydroarteannuin that patent documentation is declared; What the long-time reaction of process obtained is the more mixture of a kind of impurity, not what practical value.
Summary of the invention
Technical problem to be solved by this invention is to overcome the defective that above-mentioned prior art exists; The recoverying and utilizing method of the mother liquor that is produced in a kind of Artemether production process is provided; Be used for recycling α-Artemether, Dihydroartemisinin and the β-Artemether that mother liquor goes out of use, with the overall utilization rate of raising unit Artemisinin and the total recovery of β-Artemether.
For this reason, the present invention adopts following technical scheme: the recoverying and utilizing method of the mother liquor that is produced in a kind of Artemether production process, and its step is following:
1) the recyclable extraction that utilizes material in the Artemether mother liquor: will turn to Artemether by the Dihydroartemisinin methyl ether and wash the Artemether mother liquor that produced at vacuum, 30-50 ℃ following concentrating under reduced pressure after get rid of filtering; Steam and remove most methyl alcohol; Then add low polar organic solvent; Stir, leave standstill extraction afterwards; Branch vibration layer keeps organic layer and carries out next step reaction;
2) the recyclable conversion reaction that utilizes material: in organic layer, add the methyl alcohol of reaction solvent, 0.025～0.5 times of reaction system total solvent amount and the catalyst acid of 0.1～5% total solvent amount; React at 10～40 ℃; Reaction times is 2～24h, reacts no longer to change the back to β-Artemether content and reduce below the reacting liquid temperature to 30 ℃;
3) extraction of β-Artemether: with in the aqueous solution that alkali or alkali salt were made into the cooling after reaction solution; Regulate pH to 5～9; Leave standstill branch vibration layer after the stirring; Keep organic layer and carry out concentration; In temperature less than 50 ℃ of following concentrating under reduced pressure; Being concentrated into thick back carries secretly with anhydrous methanol; Continue to be concentrated into and do not have low polar organic solvent basically; The enriched material dissolve with methanol that obtains slowly drips purified water crystal is separated out under 0 ℃～30 ℃ temperature, drip the back and be incubated 1～2h down at-5 ℃～5 ℃; Get rid of filter; Washing, the filter cake that obtains are dried down at 50 ℃ and are the Artemether crude product, can participate in the purification operations in the production process.
The chemical equation of the principal reaction process that the present invention relates to:
Dihydroarteannuin β-Artemether
α-Artemether β-Artemether
As the further of technique scheme improved and replenish, the present invention takes following technical measures:
Above-mentioned recoverying and utilizing method; Its used raw material might not refer in particular to and turn to Artemether by the Dihydroartemisinin methyl ether in the Artemether production process and wash the Artemether mother liquor that is produced after get rid of filtering, also can be settling (containing a large amount of α-Artemethers, Dihydroartemisinin and β-Artemether) in the α-Artemether that occurs in the production process or the mother liquor pond.
Artemether mother liquor main component is a methyl alcohol, water and 1%～3% α-Artemether, Dihydroartemisinin, β-Artemether.Because α-Artemether, β-Artemether have very big solubleness in mother liquor; If without concentrating directly with organic solvent extraction; Then effect of extracting is relatively poor; And steam except that behind most of methyl alcohol through concentrating under reduced pressure; α-Artemether, the β-Artemether solubleness in water reduces greatly, can effectively improve the effect of extracting of organic solvent.
Above-mentioned recoverying and utilizing method carries out extracting and demixing when operation with low polar organic solvent in the step 1), has added the neutral inorganic salt, can many as much as possible recovery can utilize material; Described inorganic salt are sodium hydrogencarbonate, yellow soda ash, sodium-chlor, Repone K, saleratus or salt of wormwood, and peracid or mistake alkali all can cause the decomposition of reactant, reduce the recyclable utilization ratio of utilizing material.
Above-mentioned recoverying and utilizing method; Low polar organic solvent and reaction solvent are selected normal heptane for use; Methylene dichloride; Toluene; Normal hexane; Hexanaphthene; Acetonitrile; Benzene; Methylcarbonate; Pentane; Methyl acetate; Ethyl acetate or methyl propionate; Preferred toluene or normal hexane; Its input amount is 0.5～2.0 times of Artemether mother liquor amount after concentrating; Preferred 1.0 times of Artemether mother liquor amounts after concentrating; The temperature that adopts during Artemether mother liquor concentrating under reduced pressure is preferably 25-40 ℃; In the time of more than 40 ℃; The recover materials utilized contained in the mother liquor is decomposed into other impurity easily; And temperature is less than 25 ℃ the time, and methyl alcohol is difficult to be removed with steaming.According to the difference of water, methyl alcohol ratio in the mother liquor, steam till solvent-free the steaming basically, steam the rate of removing between 40%～60%.
Above-mentioned recoverying and utilizing method, step 2) the used catalyzer of conversion reaction is concentrated hydrochloric acid, sulfuric acid, perchloric acid, boron trifluoride diethyl etherate, trifluoromethanesulfonic acid, concentrated hydrochloric acid-calcium chloride system, methylsulfonic acid, phosphoric acid or tosic acid.Note drop rate when dripping some acid, if dropping is too fast, then reaction system heats up rapidly such as the vitriol oil, and acceleration can utilize the decomposition of material, improves foreign matter content, reduces its effective transformation efficiency.
Step 2) in, the usage quantity of methyl alcohol is preferably 1/6-1/20 times of reaction system total solvent amount, and the required temperature of conversion reaction is preferably 22 ℃～32 ℃, and the reaction times is preferably 5～16h, and reacting liquid temperature is preferably reduced to 10-25 ℃.Definite method of reaction end is till the content of α-Artemether and β-Artemether remains unchanged basically in its reaction solution of HPLC tracking and measuring.
In the step 3), before with alkali or the water distribution solution conditioned reaction liquid pH of alkali salt institute, need the reaction system processing of lowering the temperature.According to said step 2) used an acidic catalyst and alkali or the mixed thermal discharge of alkali salt institute water distribution solution be to the influence of reaction system, makes it to be no more than 40 ℃ to avoid the qualitative change of reactant, so reaction solution is cooled to below 30 ℃, is preferably 10 ℃～25 ℃.
Described step 3) is transferred the pH layering with the aqueous solution that alkali or alkali salt were made into; The required aqueous solution that neutralizes can be sodium hydrogen carbonate solution, sodium hydroxide solution, potassium bicarbonate solution, potassium hydroxide solution, ammoniacal liquor etc.; Concentration is 1%～5%, regulates pH to neutral, is preferably 5～9 (pH).Regulating peracid or crossing alkali to influence reaction system, reduces the recyclable utilization ratio of utilizing material.
The organic layer of described step 3) after to its layering carries out concentration, less than 50 ℃ of following concentrating under reduced pressure, is preferably 25 ℃～40 ℃ in temperature.Temperature is high more then recyclablely utilizes material apt to deteriorate, and the low then influence of temperature concentrates speed.Being concentrated into the available anhydrous methanol in a certain amount of back carries secretly and continues to be concentrated into basic organic solvent-free and steam; Have partial solvent possibly can't with methyl alcohol well carry secretly be concentrated into dried; Can continue to be evaporated to dried with adding an amount of water (v/v of 1/4 times of left and right sides methyl alcohol) behind the dissolve with methanol.Obtain thick material, contain a large amount of β-Artemethers and α-Artemether.If it is incomplete that this step concentrates, influence crystallisation process easily.
Described step 3) is used dissolve with methanol after concentrating, and methanol usage is the amount of 4～15 times (V/W) of enriched material, is preferably 5～10 times amount.Under 0 ℃～30 ℃ temperature, slowly drip purified water crystal is separated out, amount of water is confirmed as the amount of the v/v of 4/15～8.5/15 times of methyl alcohol, is preferably 6/15～7.5/15.In preferable range, the β that crystallization goes out-Artemether yield is higher, and content is purer.Drip behind the water at-5 ℃～5 ℃ insulated and stirred 1～2h, make crystallization complete as far as possible.
After described step 3) crystallization is complete, carry out the filtering and washing process, earlier with methanol-water (1: the 1) cleaning of 1/10～1/5 times of v/v amount of mother liquor, the water with equivalent cleans again behind the mother liquor suction filtration.Filter cake reduces pressure below 50 ℃ to dry and is the Artemether crude product, can participate in next step treating process, to reach production requirement.
The recrystallization process of described step 3), crystallizing system are not defined as the methanol-water system, can be ethanol-water systems, acetone-water system, normal hexane etc.
Beneficial effect of the present invention is mainly reflected in: 1. main raw material is washed the Artemether mother liquor that goes out of use that is produced for turning to Artemether by the Dihydroartemisinin methyl ether after get rid of filtering; Can recycle the α-Artemether, Dihydroartemisinin and the β-Artemether that go out of use in the mother liquor; Improve the overall utilization rate of unit Artemisinin and the total recovery of β-Artemether, it has enormous social and economic worth to suitability for industrialized production simultaneously; 2. the required low polar organic solvent of step 1) extraction can reclaim in the concentration process of step 3), can recovery set usefulness, recycle, and be applicable to cleaner production.
Embodiment
Through embodiment, further bright specifically below to technical scheme work of the present invention, but the present invention is not limited to these embodiments.
Embodiment 1
The recyclable extraction that utilizes material in the Artemether mother liquor: will turn to Artemether by the Dihydroartemisinin methyl ether and wash the mother liquor 3450ml that produced in vacuum after get rid of filtering; Temperature is less than 40 ℃ of following concentrating under reduced pressure; Steam to remove most methyl alcohol about 7h (behind about 1500ml～2000ml); (the normal heptane of input～1350ml in the concentrated solution of 1450ml～1950ml) in remainder; Leave standstill branch vibration layer (1450ml～1950ml), keep organic layer 1450ml and carry out next step reaction after stirring half an hour.
The recyclable conversion reaction that utilizes material: the four-hole boiling flask at 1000ml drops into normal heptane layer solution 450ml, and methyl alcohol 80ml and dense HCl2.5ml begin reaction under 30 ℃ of temperature condition.Each hour sampling liquid phase analysis, α-Artemether, β-Artemether content no longer change (α-Artemether is 15%～20%, and β-Artemether is 50%～55%) behind 8h～12h, begin to reduce temperature of reaction to 12 ℃～15 ℃.
The extraction of β-Artemether: the sodium hydrogen carbonate solution 200ml of adding about 5% in the reaction solution, regulate the extremely neutral back stirring of PH 30min layering, keep the normal heptane layer and carry out the concentrating under reduced pressure processing.Under 40 ℃ of following vacuum of temperature, be concentrated into thickness, can't reach thick then available anhydrous methanol and carry secretly and continue to be concentrated into basic organic solvent-free.Enriched material begins slowly to drip purified water 70ml after dissolving with methyl alcohol 150ml under 0 ℃～5 ℃ temperature, about 3h drips off.The adularescent crystal is separated out in the dropping process, drips off insulated and stirred 1h under the continued ice-water bath.Filter cake with the washing of 60ml methanol-water (1: 1) mixed system, washs with the 60ml purified water earlier again behind the suction filtration.Filter cake is the Artemether crude product 50 ℃ of oven dry of reducing pressure down, can participate in the purification operations in the production process.
Embodiment 2
The recyclable conversion reaction that utilizes material: the four-hole boiling flask at 1000ml drops into normal heptane layer solution 450ml, and methyl alcohol 80ml and perchloric acid 2.5ml begin reaction under 30 ℃ of temperature condition.Each hour sampling liquid phase analysis, α-Artemether, β-Artemether content no longer change (α-Artemether is 12%～16%, and β-Artemether is 57%～62%) behind 6h～8h, begin to reduce temperature of reaction to 12 ℃～15 ℃.
The extraction of β-Artemether: the sodium hydrogen carbonate solution 200ml of adding about 5% in the reaction solution, regulate the extremely neutral back stirring of PH 30min layering, keep the normal heptane layer and carry out the concentrating under reduced pressure processing.Under 40 ℃ of following vacuum of temperature, be concentrated into thickness, can't reach thick then available anhydrous methanol and carry secretly to basic organic solvent-free.Last concentrating can be taked to dissolve dope fully with methyl alcohol and added suitable quantity of water and continue concentrating under reduced pressure.Enriched material begins slowly to drip purified water 75ml after dissolving with methyl alcohol 150ml under ambient temperature, about 3h drips off.The adularescent crystal is separated out in the dropping process, drips off insulated and stirred 2h under the ice-water bath of back.Filter cake with the washing of 60ml methanol-water (1: 1) mixed system, washs with the 60ml purified water earlier again behind the suction filtration.Filter cake is the Artemether crude product 50 ℃ of oven dry of reducing pressure down, can participate in the purification operations in the production process.
Embodiment 3
The recyclable conversion reaction that utilizes material: the four-hole boiling flask at 1000ml drops into normal heptane layer solution 450ml, and methyl alcohol 80ml and vitriol oil 2.5ml begin reaction under 30 ℃ of temperature condition.Each hour sampling liquid phase analysis, α-Artemether, β-Artemether content no longer change (α-Artemether is 12%～18%, and β-Artemether is 57%～66%) behind 4h～7h, begin to reduce temperature of reaction to 12 ℃～15 ℃.
The extraction of β-Artemether: the sodium hydrogen carbonate solution 200ml of adding about 5% in the reaction solution, regulate the extremely neutral back stirring of PH 30min layering, keep the normal heptane layer and carry out the concentrating under reduced pressure processing.Under 40 ℃ of following vacuum of temperature, be concentrated into thickness, can't reach thick then available anhydrous methanol and carry secretly to basic organic solvent-free.Last concentrating can be taked to dissolve dope fully with methyl alcohol and added suitable quantity of water and continue concentrating under reduced pressure.Enriched material with methyl alcohol 150ml and 50ml water dissolution after, under 30 ℃ of temperature, begin to be evaporated to the adularescent crystal and separate out, continue to concentrate back solution gradually to thick excessively, stop to concentrate the back and slowly drip about 150ml methyl alcohol to crystal and dissolve fully.Be evaporated to the adularescent crystal once more and separate out, becoming sticky at white crystal stops to concentrate before thick.Insulated and stirred 2h under the ice-water bath.Filter cake with the washing of 60ml methanol-water (1: 1) mixed system, washs with the 60ml purified water earlier again behind the suction filtration.Filter cake is the Artemether crude product 50 ℃ of oven dry of reducing pressure down, can participate in the purification operations in the production process.
Embodiment 4
The recyclable extraction that utilizes material in the Artemether mother liquor: will turn to Artemether by the Dihydroartemisinin methyl ether and wash the mother liquor 3450ml that produced in vacuum after get rid of filtering; Temperature is less than 40 ℃ of following concentrating under reduced pressure; Steam to remove most methyl alcohol about 7h (behind about 1500ml～2000ml); (the toluene of input～1350ml in the concentrated solution of 1450ml～1950ml) in remainder; Leave standstill branch vibration layer (1450ml～1950ml), keep organic layer 1450ml and carry out next step reaction after stirring half an hour.
The recyclable conversion reaction that utilizes material: the four-hole boiling flask at 1000ml drops into toluene layer solution 450ml, and methyl alcohol 40ml and vitriol oil 2.5ml begin reaction under 30 ℃ of temperature condition.Each hour sampling liquid phase analysis, α-Artemether, β-Artemether content no longer change (α-Artemether is 13%～17%, and β-Artemether is 55%～59%) behind 4h～6h, begin to reduce temperature of reaction to 12 ℃～15 ℃.
The extraction of β-Artemether: regulate the extremely neutral back of PH with about 2% sodium hydroxide solution in the reaction solution and stir the 30min layering, keep toluene layer and carry out the concentrating under reduced pressure processing.Under 40 ℃ of following vacuum of temperature, be concentrated into thickness, can't reach thick then available anhydrous methanol and carry secretly to basic organic solvent-free.Last concentrating can be taked to dissolve dope fully with methyl alcohol and added suitable quantity of water and continue concentrating under reduced pressure.Enriched material with methyl alcohol 150ml and 50ml water dissolution after, under 30 ℃ of temperature, begin to be evaporated to the adularescent crystal and separate out, continue to concentrate back solution gradually to thick excessively, stop to concentrate the back and slowly drip about 150ml methyl alcohol to crystal and dissolve fully.Be evaporated to the adularescent crystal once more and separate out, becoming sticky at white crystal stops to concentrate before thick.Insulated and stirred 2h under the ice-water bath.Filter cake with the washing of 60ml methanol-water (1: 1) mixed system, washs with the 60ml purified water earlier again behind the suction filtration.Filter cake is the Artemether crude product 50 ℃ of oven dry of reducing pressure down, can participate in the purification operations in the production process.
Embodiment 5
The recyclable conversion reaction that utilizes material: the four-hole boiling flask at 1000ml drops into toluene layer solution 450ml, and methyl alcohol 40ml and concentrated hydrochloric acid 2.5ml begin reaction under 30 ℃ of temperature condition.Each hour sampling liquid phase analysis, α-Artemether, β-Artemether content no longer change (α-Artemether is 12%～16%, and β-Artemether is 53%～55%) behind 4h～6h, begin to reduce temperature of reaction to 12 ℃～15 ℃.
The extraction of β-Artemether: the sodium hydrogen carbonate solution 200ml of adding about 5% in the reaction solution, regulate the extremely neutral back stirring of PH 30min layering, keep toluene layer and carry out the concentrating under reduced pressure processing.Under 40 ℃ of following vacuum of temperature, be concentrated into thickness, can't reach thick then available anhydrous methanol and carry secretly to basic organic solvent-free.Last concentrating can be taked to dissolve dope fully with methyl alcohol and added suitable quantity of water and continue concentrating under reduced pressure.Enriched material begins slowly to drip purified water 180ml after dissolving with ethanol 150ml under ambient temperature, about 3h drips off.The adularescent crystal is separated out in the dropping process, drips off insulated and stirred 2h under the ice-water bath of back.Filter cake with the washing of 60ml alcohol-water (1: 1) mixed system, washs with the 60ml purified water earlier again behind the suction filtration.Filter cake is the Artemether crude product 50 ℃ of oven dry of reducing pressure down, can participate in the purification operations in the production process.
Embodiment 6
The recyclable extraction that utilizes material in the Artemether mother liquor: will turn to Artemether by the Dihydroartemisinin methyl ether and wash the mother liquor 3450ml that produced in vacuum after get rid of filtering; Temperature is less than 40 ℃ of following concentrating under reduced pressure; Steam to remove most methyl alcohol about 7h (behind about 1500ml～2000ml); (the normal hexane of input～1350ml in the concentrated solution of 1450ml～1950ml) in remainder; Leave standstill branch vibration layer (1450ml～1950ml), keep organic layer 1450ml and carry out next step reaction after stirring half an hour.
The recyclable conversion reaction that utilizes material: the four-hole boiling flask at 1000ml drops into normal hexane layer solution 450ml, and methyl alcohol 40ml and boron trifluoride diethyl etherate 2.5ml begin reaction under 30 ℃ of temperature condition.Each hour sampling liquid phase analysis, α-Artemether, β-Artemether content no longer change (α-Artemether is 10%～15%, and β-Artemether is 55%～62%) behind 8h～14h, begin to reduce temperature of reaction to 12 ℃～15 ℃.
The extraction of β-Artemether: the sodium hydrogen carbonate solution 200ml of adding about 5% in the reaction solution, regulate the extremely neutral back stirring of PH 30min layering, keep toluene layer and carry out the concentrating under reduced pressure processing.Under 40 ℃ of following vacuum of temperature, be concentrated into thickness, can't reach thick then available anhydrous methanol and carry secretly to basic organic solvent-free.Last concentrating can be taked to dissolve dope fully with methyl alcohol and added suitable quantity of water and continue concentrating under reduced pressure.Enriched material begins slowly to drip purified water 70ml after dissolving with methyl alcohol 150ml under ambient temperature, about 3h drips off.The adularescent crystal is separated out in the dropping process, drips off insulated and stirred 2h under the ice-water bath of back.Filter cake with the washing of 60ml methanol-water (1: 1) mixed system, washs with the 60ml purified water earlier again behind the suction filtration.Filter cake is the Artemether crude product 50 ℃ of oven dry of reducing pressure down, can participate in the purification operations in the production process.
The above only is a preferred embodiments of the present invention, is not the present invention is done any pro forma restriction.Any simple modification that every technical scheme essence according to the present invention is done, equivalent variations and modification all fall into protection scope of the present invention.
Claims (10)
1. the recoverying and utilizing method of the mother liquor that is produced in the Artemether production process, its step is following:
1) the recyclable extraction that utilizes material in the Artemether mother liquor: will turn to Artemether by the Dihydroartemisinin methyl ether and wash the Artemether mother liquor that produced at vacuum, 30-50 ℃ following concentrating under reduced pressure after get rid of filtering; Steam and remove most methyl alcohol; Then add low polar organic solvent; Stir, leave standstill extraction afterwards; Branch vibration layer keeps organic layer and carries out next step reaction;
2) the recyclable conversion reaction that utilizes material: in organic layer, add the methyl alcohol of reaction solvent, 0.025～0.5 times of reaction system total solvent amount and the catalyst acid of 0.1～5% total solvent amount; React at 10～40 ℃; Reaction times is 2～24h, reacts no longer to change the back to β-Artemether content and reduce below the reacting liquid temperature to 30 ℃;
3) extraction of β-Artemether: with in the aqueous solution that alkali or alkali salt were made into the cooling after reaction solution; Regulate pH to 5～9; Leave standstill branch vibration layer after the stirring; Keep organic layer and carry out concentration; In temperature less than 50 ℃ of following concentrating under reduced pressure; Being concentrated into thick back carries secretly with anhydrous methanol; Continue to be concentrated into and do not have low polar organic solvent basically; The enriched material dissolve with methanol that obtains; Under 0 ℃～30 ℃ temperature, slowly drip purified water crystal is separated out, drip the back and be incubated 1～2h down, get rid of filter at-5 ℃～5 ℃; Washing, the filter cake that obtains are dried down at 50 ℃ and are the Artemether crude product.
2. recoverying and utilizing method according to claim 1 is characterized in that, carries out extracting and demixing when operation with low polar organic solvent in the step 1), has added the neutral inorganic salt.
3. recoverying and utilizing method according to claim 2 is characterized in that, described inorganic salt are sodium hydrogencarbonate, yellow soda ash, sodium-chlor, Repone K, saleratus or salt of wormwood.
4. recoverying and utilizing method according to claim 1; It is characterized in that; Described low polar organic solvent and reaction solvent are selected normal heptane, methylene dichloride, toluene, normal hexane, hexanaphthene, acetonitrile, benzene, methylcarbonate, pentane, methyl acetate, ethyl acetate or methyl propionate for use, and its input amount is 0.5～2.0 times of Artemether mother liquor amount after concentrating.
5. recoverying and utilizing method according to claim 4; It is characterized in that; Described low polar organic solvent and reaction solvent are selected toluene or normal hexane for use, and its input amount is 1.0 times of Artemether mother liquor amounts after concentrating, and the temperature that adopts during Artemether mother liquor concentrating under reduced pressure is 25-40 ℃.
6. recoverying and utilizing method according to claim 1 is characterized in that, the used raw material of step 1) adopts that settling replaces in the α-Artemether that occurs in the Artemether production process or the mother liquor pond.
7. recoverying and utilizing method according to claim 1 is characterized in that step 2) in; The usage quantity of methyl alcohol is 1/6-1/20 a times of reaction system total solvent amount; The required temperature of conversion reaction is 22 ℃～32 ℃, and the reaction times is 5～16h, and reacting liquid temperature is reduced to 10-25 ℃.
8. recoverying and utilizing method according to claim 1; It is characterized in that step 2) the used catalyst acid of conversion reaction is any in concentrated hydrochloric acid, sulfuric acid, perchloric acid, boron trifluoride diethyl etherate, trifluoromethanesulfonic acid, concentrated hydrochloric acid-calcium chloride system, methylsulfonic acid, phosphoric acid, the tosic acid.
9. recoverying and utilizing method according to claim 1; It is characterized in that; In the step 3); The required aqueous solution of neutralization reaction liquid was sodium hydrogen carbonate solution, sodium hydroxide solution, potassium bicarbonate solution, potassium hydroxide solution or ammoniacal liquor when β-Artemether extracted; The organic layer concentrating under reduced pressure is at 25～40 ℃; Behind the concentrating under reduced pressure, the methanol usage that dissolving is used is 4～15 times of enriched material; The add-on of purified water is 4/15～8.5/15 times of methanol usage.
10. recoverying and utilizing method according to claim 1 is characterized in that, in the step 3), the add-on of purified water is 6/15～7.5/15 times of methanol usage.
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Cited By (2)
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| CN103333177A (en) * | 2013-07-03 | 2013-10-02 | 重庆启哲生物科技有限公司 | Method for preparing beta-artemether artemether from artemether mother liquor |
| CN104910173A (en) * | 2015-06-12 | 2015-09-16 | 重庆华方武陵山制药有限公司 | Treatment method for artesunate crystallization mother liquid |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103333177A (en) * | 2013-07-03 | 2013-10-02 | 重庆启哲生物科技有限公司 | Method for preparing beta-artemether artemether from artemether mother liquor |
| CN103333177B (en) * | 2013-07-03 | 2016-01-27 | 重庆恒星生物技术有限责任公司 | A kind of Artemether mother liquor prepares the method for β-Artemether |
| CN104910173A (en) * | 2015-06-12 | 2015-09-16 | 重庆华方武陵山制药有限公司 | Treatment method for artesunate crystallization mother liquid |
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