WO2020207130A1 - 一种青蒿素分离纯化工艺 - Google Patents

一种青蒿素分离纯化工艺 Download PDF

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WO2020207130A1
WO2020207130A1 PCT/CN2020/076403 CN2020076403W WO2020207130A1 WO 2020207130 A1 WO2020207130 A1 WO 2020207130A1 CN 2020076403 W CN2020076403 W CN 2020076403W WO 2020207130 A1 WO2020207130 A1 WO 2020207130A1
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artemisinin
extract
separation
alcohol
purification process
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PCT/CN2020/076403
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English (en)
French (fr)
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张梅
赵金召
赵金全
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湖南斯依康生物科技有限公司
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Priority to US17/610,442 priority Critical patent/US20220204522A1/en
Publication of WO2020207130A1 publication Critical patent/WO2020207130A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/20—Spiro-condensed systems

Definitions

  • the invention belongs to the technical field of artemisinin separation and purification, and specifically relates to an artemisinin separation and purification process.
  • Artemisinin also known as artemisinin, is a sesquiterpene lactone compound with peroxy bridge extracted and isolated from the leaves of the Compositae plant Artemisia annua by Chinese pharmaceutical workers in 1971.
  • the preparation process of artemisinin mainly includes plant extraction, biosynthesis, chemical synthesis and plant tissue culture.
  • the direct extraction of artemisinin from Artemisia annua can extract its active ingredients according to the solubility differences of various components in Chinese herbal medicines in different solvents. How to extract artemisinin more efficiently and reduce the energy loss in the extraction process while ensuring the purity of the product is a technical problem that needs to be solved in this field.
  • Chinese patent application CN201711142287.1 discloses a method for purifying artemisinin, which includes the following steps: S1. Artemisia annua extract is separated and purified by a column to obtain a column eluate; S2. Concentrate at -85°C, and the volume after concentration is 1/10-1/20 of that before concentration. After standing for crystallization, take out the crude product and dry it for later use; S3. Add alcohol to the crude product, dissolve, stand for crystallization, filter, Take the crystal to get artemisinin.
  • the artemisinin purification method provided by this patent can effectively reduce the content of impurity B and control the content of impurity B to less than 0.2%.
  • the purification method adopts column separation method for purification, it is not conducive to large-scale industrial production, and the recovery rate of artemisinin is low.
  • Another example is the Chinese patent application CN201110114772.4 discloses a green extraction process of artemisinin, which includes (1) drying treatment of raw materials; (2) preliminary production of artemisinin: the treated raw materials are extracted with petroleum ether and then separated , The supernatant was eluted through a silica gel column, and the obtained eluate was concentrated to the precipitation of crystals, crystallized in a crystallization tank for 15-20 hours, after the crystallization was completed, filtered to obtain crude artemisinin crystals; (3) Artemisinin purification : Put the crude artemisinin crystals obtained in step (2) in an alcohol precipitation tank to dissolve and stand still, take the supernatant and filter it roughly, concentrate the filtrate, and remove the mother liquor after crystallization for 15-20 hours to obtain the fine artemisinin.
  • the problem to be solved by the present invention is to provide an artemisinin separation and purification process with high yield, high purity, low energy consumption rate in the purification process and low pollution.
  • the present invention provides an artemisinin separation and purification process, which includes the following steps:
  • the artemisinin petroleum ether extract is concentrated to 1/10-1/50 of the original volume and then filtered under pressure to obtain the artemisinin crude crystal 1, mother liquor 1, and the mother liquor 1 is concentrated under reduced pressure to obtain the artemisinin extract 1.
  • the content of artemisinin in the artemisinin petroleum ether extract is 0.1%-1%;
  • step S3 Repeat step S2 once for the artemisinin extract 2 to obtain an alcohol-water extract 2 and artemisinin extract 3;
  • the concentration temperature in S1 is 50-70°C. Concentrating at this temperature can ensure the rapid removal of the solvent without affecting the structure of the active ingredients in the extract. The test results show that when the temperature is higher than 70°C, the yield of the finished artemisinin is significantly reduced.
  • the volume fraction of the aqueous alcohol solution in S2 is 10-50%, and the alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol.
  • the content of artemisinin in the petroleum ether extract of artemisinin in S1 is 0.1%-0.5%.
  • the main components in the extract are artemisinin, artemisinin B, artemisinin C, artemisinic acid and dihydroartemisinic acid.
  • the content of artemisinin in the petroleum ether extract of artemisinin in S1 is 0.15%.
  • the preparation process of the artemisia annua petroleum ether extract includes the following steps:
  • the Artemisia annua leaf is mixed with petroleum ether equivalent to 3-10 times its volume, heated and extracted at 40-50°C for 4-8 hours, repeated 2-3 times, and the extracts are combined to obtain the Artemisia annua petroleum ether extract.
  • the alcohol solvent in S5 is methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol.
  • the alcohol solvent in S5 is isopropanol, n-butanol or tert-butanol.
  • the amount used when dissolving the crude artemisinin is 20%-50% of the amount used when using other solvents, which can reduce the amount of organic solvents, save production costs, and reduce the dissolution loss of artemisinin. Improve the recovery rate of fine products.
  • the volume-mass ratio of the alcohol aqueous solution to the artemisinin extract 1 in S2 is 4-6:1.
  • the cooling described in S5 is gradient cooling, and the specific operation is: first naturally cool down to room temperature and continue to heat and stir for 40-70 minutes; then cool down to 15-20°C within 1-2 hours and continue to heat and stir for 40-70 minutes; Cool down to 0-10°C within 1-2h and continue to keep heat and stir for 1.5-3h.
  • the use of gradient cooling is conducive to obtaining a good crystal form of the artemisinin crystal, and the cooling time is controlled within 1-2h, which is conducive to the formation of artemisinin crystals with better purity and better crystal form.
  • the stirring speed during the gradient cooling in step S5 is 10-30 rad/min.
  • the specific filtering operation in step S5 is: sequentially performing filler adsorption filtering and filter bag fine filtering, and the filler is diatomaceous earth or activated carbon. Petroleum ether is used for washing during filtration. This filtration step can remove some insoluble impurities.
  • a double cone dryer is used for drying in step S5, the drying temperature is 40-60°C, and the drying time is 3-6 hours.
  • the drying temperature is 50°C, and the drying time is 3-5 hours.
  • the artemisinin extract 3 repeats step S2 at least once to obtain the artemisinin extract and the alcohol-water extract N, and the alcohol-water extract N is used to dissolve the green in the next batch of step S2.
  • the concentrated solution is naturally cooled to 25-35° C. while stirring, and the temperature is maintained and stirred for 1-2 hours. If stirring is not performed during the cooling process, it can ensure that the artemisinin crystallization process will not be too fast, thereby avoiding the inclusion of impurities; and this preferred solution adopts the method of stirring and crystallization, and at the same time continues after the natural cooling to 25-35°C Heat preservation and stirring for 1-2h, and finally obtain coarse artemisinin crystals 1 through pressure filtration.
  • the cooling rate and the stirring time are controlled, which is beneficial to the formation of artemisinin crystals with good crystal form and uniform quality without impurities.
  • step S2 the following operations are carried out before the pressure filtration in step S2: the artemisinin extract 1 is added to the alcohol aqueous solution and heated to 25-80°C, stirred and dissolved for 1-2 hours, and then cooled to 15-40°C.
  • step S4 the specific operation of cooling and crystallization in step S4 is: cooling to -5 to 10° C., crystallization for 1-2 hours.
  • the mother liquor 2 is concentrated to recover the alcohol solvent and used in step S5. Recycling the recovered alcohol solvent can reduce the solvent loss rate and save production costs.
  • the artemisinin separation and purification process provided by the present invention has the following beneficial effects:
  • the recovery rate of the fine artemisinin obtained by the artemisinin separation and purification process provided in this application can reach 75%; the purity can reach more than 98%; the crystal structure is regular, and the crystal grains are needle-like crystals of 0.5-1 cm.
  • the melting range of artemisinin is 151-153°C.
  • the meaning of the yield of fine artemisinin refers to the quality of fine artemisinin in the leaves of Artemisia annua per unit weight/theoretical mass of artemisinin ⁇ 100%.
  • the theoretical content of artemisinin in Artemisia annua is 15kg per ton.
  • the purity of fine artemisinin refers to the percentage of the quality of artemisinin in fine artemisinin relative to the quality of fine artemisinin.
  • a separation and purification process for artemisinin includes the following steps:
  • the petroleum ether extract of Artemisia annua L was concentrated to 1/40 of its original volume under normal pressure and a temperature of 50°C, and then the temperature was naturally cooled to 25°C while stirring, and the temperature was maintained and stirred for 1 hour before pressure filtration to obtain artemisinin Crude crystal 1, mother liquor 1, the mother liquor 1 is concentrated under reduced pressure to dryness to obtain artemisinin extract 1, wherein the artemisinin content in the artemisinin petroleum ether extract is 0.15%;
  • the alcohol aqueous solution is a methanol solution with a volume fraction of 10%, and the mass volume ratio of artemisinin extract 1 to the alcohol aqueous solution is 5;
  • the artemisinin extract 2 is used S2 once to obtain the alcohol-water extract 2 and the artemisinin extract 3; the artemisinin extract 3 repeats step S2 twice to obtain the artemisinin extract And alcohol-water extract N, which is used to dissolve the artemisinin extract 1 in the next batch of step S2;
  • the alcohol solvent is tert-butanol, and the mass volume ratio of the alcohol solvent to the crude crystal mixture is 20L/kg;
  • the gradient cooling process is as follows: first naturally cool down to room temperature and continue stirring for 1h; then cool down to 15°C within 1h and continue stirring for 1h; then cool down to 0°C within 1h and continue stirring for 2h.
  • the stirring speed is 10rad/min.
  • the yield of the fine artemisinin was 75%, the purity was 98.7%, and the single impurity was not more than 1%.
  • the alcohol solvent in step S5 is ethanol.
  • the yield of the fine artemisinin is 69%, the purity is 96.4%, and the single impurity is not more than 1%.
  • a separation and purification process for artemisinin includes the following steps:
  • the alcohol aqueous solution is a 10% tert-butanol solution with a volume fraction of 10%, and the mass volume ratio of artemisinin extract 1 to the alcohol aqueous solution is 4;
  • the artemisinin extract 2 is used S2 once to obtain the alcohol-water extract 2 and the artemisinin extract 3; the artemisinin extract 3 repeats step S2 once to obtain the artemisinin extract and Alcohol-water extract N, which is used to dissolve the artemisinin extract 1 in the next batch of step S2;
  • the gradient cooling process is as follows: firstly cool down to room temperature and continue stirring for 1h; then cool down to 15°C within 1h and continue stirring for 1h; then cool down to 0°C within 1h and continue stirring for 2h.
  • the stirring speed during gradient cooling is 30rad/ min;
  • the alcohol solvent is isopropanol, and the mass volume ratio of the alcohol solvent to the crude crystal mixture is 50 L/kg.
  • the yield of the fine artemisinin is 74%, the purity is 98.7%, and the single impurity is not more than 1%.
  • step S5 The operation of step S5 is: the artemisinin coarse crystal 1 and the artemisinin coarse crystal 2 are combined, mixed with an alcohol solvent, heated and stirred at 30°C to dissolve, then the jacket is cooled to 0°C, and then the filler (silicon Algae earth) adsorption filtration, filter bag fine filtration; the filtrate after fine filtration is heated to 40°C and concentrated under reduced pressure.
  • the volume-mass ratio of the concentrated liquid and the crude crystal mixture before concentration is 5L/kg,
  • the yield of the fine artemisinin is 65%, the purity is 93%, and the single impurity is not more than 2%.
  • the stirring speed during the gradient cooling in step S5 is 50 rad/min.
  • the yield of fine artemisinin was 73%, the purity was 96.6%, and the single impurity was not more than 1%.
  • the gradient cooling process in step S5 is as follows: first naturally cool to room temperature and continue stirring for 1 hour; then cool to 15° C. within 5 hours and continue stirring for 1 hour; then cool to 0° C. within 5 hours and continue stirring for 2 hours.
  • the yield of the fine artemisinin is 71%, the purity is 96%, and the single impurity is not more than 1%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

本发明属于青蒿素分离纯化技术领域，具体涉及一种青蒿素分离纯化工艺。该分离纯化工艺包括如下步骤：S1.将青蒿提取液浓缩、压滤，得到青蒿素粗晶1、母液1，将母液1减压浓缩后得到青蒿素浸膏1；S2.将青蒿素浸膏1加入醇水溶液中搅拌溶散后分离，得到醇水提取液1和青蒿素浸膏2；S3.将青蒿素浸膏2重复S2后得醇水提取液2和青蒿素浸膏3；S4.将醇水提取液1和2合并后降温、结晶、压滤，得青蒿素粗结晶2、母液2；S5.将青蒿素粗晶1和2合并后用醇类溶剂溶解，过滤，将滤液加热后减压浓缩，冷却、压滤、干燥得青蒿素精品。本发明提供的分离纯化工艺产品回收率高、纯度高，晶型质量高。

Description

一种青蒿素分离纯化工艺 技术领域
本发明属于青蒿素分离纯化技术领域，具体涉及一种青蒿素分离纯化工艺。
背景技术
青蒿素又名黄蒿素，是我国药学工作者1971年从菊科植物黄花蒿叶中提取分离到的一种具有过氧桥的倍半萜内酯类化合物。青蒿素的制备工艺主要有植物提取、生物合成、化学合成和植物组织培养。从黄花蒿中直接提取青蒿素可以根据中草药中的各类成分在不同溶剂中的溶解度差异，从而将其有效成分提取出来。如何能够更高效地提取青蒿素，并且在降低提取过程中的能源损耗的同时，保证产品的纯度是本领域需要解决的技术问题。
经检索，已有较多关于青蒿素提取、分离纯化方法方面的报道。如中国专利申请CN201711142287.1公开了一种青蒿素的纯化方法，其包括以下步骤：S1.青蒿提取液经过柱分离纯化后，得到柱洗脱液；S2.取柱洗脱液在40-85℃下进行浓缩，浓缩后的体积是浓缩前的1/10-1/20，静置结晶后取出粗品烘干，备用；S3.往粗品中加入醇，溶解，静置结晶，过滤，取结晶体，得青蒿素。该专利提供的青蒿素纯化方法，能有效的将杂质B的含量降低，控制杂质B的含量低于0.2％。但是由于该纯化方法采用柱分离方法进行纯化，不利于大规模工业化生产，而且青蒿素的回收率较低。
又如中国专利申请CN201110114772.4公开了一种青蒿素绿色提取工艺，其包括(1)原料的干燥处理；(2)青蒿素的初制：将处理后的原料采用石油醚提取后分离，上清液过硅胶柱洗脱，所得洗脱液浓缩至有晶体析出时，在结晶罐中结晶15-20小时，结晶完成后过滤得青蒿素粗晶；(3)青蒿素的精制：将步骤(2)得到的青蒿素粗晶置于醇沉罐中溶解静置，取上清液粗密过滤，滤液浓缩，结晶15-20小时后除去母液得青蒿素精品。该方法节能、降耗，解决了青蒿素在提取过程中受热分解而影响收率的问题，但工艺流程耗时长，如每次结晶都在15小时以上，严重影响了实验效率；而且其中使用硅胶柱进行纯化，使得青蒿素的收率较低。
发明内容
本发明要解决的问题是提供一种收率高、纯度高，并且提纯过程能源损耗率低、污染小的青蒿素分离纯化工艺。
为解决上述问题，本发明提供了一种青蒿素分离纯化工艺，包括以下步骤：
S1.将青蒿石油醚提取液浓缩至原体积的1/10-1/50后压滤，得到青蒿素粗晶1、母液1，所述母液1减压浓缩后得到青蒿素浸膏1，其中，所述青蒿石油醚提取液中青蒿素的含量为0.1％-1％；
S2.将所述青蒿素浸膏1加入醇水溶液中搅拌溶散后压滤或者离心分离，得到醇水提取液1和青蒿素浸膏2；
S3.将所述青蒿素浸膏2重复步骤S2一次后得醇水提取液2和青蒿素浸膏3；
S4.将醇水提取液1和2合并后降温、结晶、压滤，得青蒿素粗结晶2、母液2；
S5.将所述青蒿素粗晶1、青蒿素粗晶2合并后采用醇类溶剂溶解，过滤，将所得滤液升温至40-70℃后减压浓缩，浓缩后液体与浓缩前粗晶混合物的体积质量比为5-20L/kg，冷却、压滤、干燥得青蒿素精品；其中醇类溶剂与青蒿素粗晶混合物的体积质量比为20-100L/kg。
优选地，S1中浓缩温度为50-70℃。在该温度下浓缩可以保证快速除去溶剂的同时，不影响提取液中有效成分的结构。试验结果表明，温度高于70℃时，青蒿素成品的收率明显降低。
优选地，S2中所述醇水溶液的体积分数为10-50％，醇为甲醇、乙醇、正丙醇、异丙醇、正丁醇或叔丁醇。
优选地，所述S1中青蒿石油醚提取液中青蒿素的含量为0.1％-0.5％。
所述提取液中主要成分为青蒿素、青蒿乙素、青蒿丙素、青蒿酸和二氢青蒿酸。
在本发明的一个优选实施例中，所述S1中青蒿石油醚提取液中青蒿素的含量为0.15％。
优选地，所述青蒿石油醚提取液的制备工艺，其包括如下步骤：
将青蒿叶与相当于其体积3-10倍量的石油醚混合，于40-50℃加热提取4-8小时，重复2-3次，合并提取液即得青蒿石油醚提取液。
优选地，S5中所述醇类溶剂为甲醇、乙醇、正丙醇、异丙醇、正丁醇或叔丁醇。
进一步优选地，S5中所述醇类溶剂为异丙醇、正丁醇或叔丁醇。采用该优选方案时溶解青蒿素粗品时的使用量为使用其它溶剂时的使用量的20％-50％，可以减少有机溶剂的用量，节约生产成本，而且降低了青蒿素的溶解损失，提高了精品回收率。
优选地，S2中所述醇水溶液与青蒿素浸膏1的体积质量比为4-6:1。
优选地，S5所述冷却为梯度降温冷却，具体操作为：先自然降温至室温并继续保温搅拌40-70min；随后在1-2h内降温至15-20℃并继续保温搅拌40-70min；随后在1-2h内降温至0-10℃并继续保温搅拌1.5-3h。
采用梯度降温，有利于青蒿素晶体得到良好的晶型，并且将降温时间控制在1-2h，有利于形成纯度更好、晶型更好的青蒿素晶体。
进一步优选地，步骤S5梯度降温时的搅拌速度为10-30rad/min。在如上搅拌速度范围时有利于形成较好的青蒿素晶型，并使针状晶型粒度较大，而且产品含量高、纯度高。
优选地，步骤S5中所述过滤具体操作为：依次进行填料吸附过滤和滤袋精滤，所述填料为硅藻土或活性炭。过滤时采用石油醚进行洗涤，该过滤步骤可除去一些不溶性杂质。
优选地，步骤S5中干燥采用双锥烘干机，干燥温度为40-60℃，干燥时间为3-6h。
进一步优选地，所述干燥温度为50℃，干燥时间为3-5h。
优选地，所述青蒿素浸膏3重复步骤S2至少一次后得青蒿素浸膏和醇水提取液N，所述醇水提取液N用于下一批步骤S2中溶散所述青蒿素浸膏1。
优选地，步骤S1压滤之前进行如下操作：浓缩后的溶液边搅拌边自然降温至25-35℃，并继续保温搅拌1-2h。如果在降温过程中不进行搅拌，可以保证青蒿素结晶过程不会过快，从而避免包裹杂质；而该优选方案采用边搅拌、边结晶的方式，同时在自然降温至25-35℃后继续保温搅拌1-2h，最终经过压滤得到青蒿素粗晶1，控制了降温速度以及搅拌的时间，有利于形成晶型好、且质量均匀不含杂质的青蒿素晶体。
优选地，步骤S2压滤前进行如下操作：将所述青蒿素浸膏1加入醇水溶液中加热至25-80℃，搅拌溶散1-2h，然后降温至15-40℃。
优选地，步骤S4所述的降温、结晶的具体操作为：降温至-5至10℃，结晶1-2h。
优选地，所述母液2经浓缩后回收醇溶剂并用于步骤S5。将回收后的醇溶剂回收利用可以降低溶剂损耗率，节约生产成本。
与现有技术相比，本发明提供的青蒿素的分离纯化工艺具有如下有益效果：
(1)现有技术中在进行工业生产时，需要将提取液经过柱分离纯化后再进行浓缩，该过程需要使用硅胶柱层分析法分离、纯化青蒿素，需要使用大量硅胶，使硅胶的损耗增加成本较大，并且装柱、卸柱较为复杂，还需消耗大量的有机溶剂(石油醚和/乙酸乙酯)进行洗脱，存在较高的安全风险；本申请无需使用柱分离，一方面简化了工艺流程，并且减少了硅胶的使用量节约了成本，另一方面降低了安全风险，本申请直接结晶可以先回收50-60％的青蒿素；
(2)本申请提供的青蒿素的分离纯化工艺得到的青蒿素精品的回收率可以达到75％；纯度可以达到98％以上；晶型规整，晶粒为0.5-1cm的针状晶体。青蒿素熔程是151-153℃。
具体实施方式
下面对本发明做进一步说明，并给出本发明的实施例。
本发明中，青蒿素精品收率的含义是指单位重量的青蒿叶中青蒿素精品质量/青蒿素理论质量×100％，比如青蒿中青蒿素的理论含量为15kg每吨，经本申请提供的分离纯化工艺得到14.5kg，则青蒿素精品收率为14.5/15×100％＝96.67％。
青蒿素精品纯度是指青蒿素精品中青蒿素质量相对于青蒿素精品质量的百分比。
实施例1
一种青蒿素分离纯化工艺，包括以下步骤：
S1.将青蒿石油醚提取液在常压、温度为50℃条件下浓缩至原体积的1/40，然后边搅拌边自然降温至25℃并继续保温搅拌1h后压滤，得到青蒿素粗晶1、母液1，所述母液1经过减压浓缩至干得到青蒿素浸膏1，其中所述青蒿石油醚提取液中青蒿素的含量为0.15％；
S2.将所述青蒿素浸膏1加入醇水溶液中加热至25℃，搅拌溶散1h，然后降温至15℃，压滤，得到醇水提取液1和青蒿素浸膏2，其中，醇水溶液为体积分数为10％的甲醇溶液，青蒿素浸膏1与醇水溶液的质量体积比为5；
S3.将所述青蒿素浸膏2使用S2一次后得到和醇水提取液2和青蒿素浸膏3；所述青蒿素浸膏3重复步骤S2两次后得青蒿素浸膏和醇水提取液N，所述醇水提取液N用于下一批步骤S2中溶散所述青蒿素浸膏1；
S4.将所述醇水提取液1和所述醇水提取液2合并后搅拌降温至-5℃并在该温度下结晶1h，压滤，得到青蒿素粗结晶2、母液2；
S5.将所述青蒿素粗晶1、青蒿素粗晶2合并后与醇类溶剂混合后于30℃加热搅拌溶解，随后夹套制冷至0℃，再进行填料(硅藻土)吸附过滤、滤袋精滤；将精滤后的滤液加热至40℃后减压浓缩，浓缩后液体与浓缩前粗晶混合物的体积质量比为5L/kg，再梯度降温冷却至0℃，压滤，压滤后所得固体于50℃采用双锥烘干机烘干3h后得到青蒿素精品；
其中所述醇类溶剂为叔丁醇，醇类溶剂与粗晶混合物的质量体积比为20L/kg；
所述梯度降温过程如下：首先自然降温至室温，并继续搅拌1h；随后在1h内降温至15℃，并继续搅拌1h；随后在1h内降温至0℃，并继续搅拌2h，梯度降温时的搅拌速度为10rad/min。
本实施例中，青蒿素精品的收率为75％，纯度为98.7％，且单个杂质不大于1％。
实施例2
一种青蒿素分离纯化工艺，其与实施例1的区别在于，
步骤S5中所述醇类溶剂为乙醇。
本实施例中，青蒿素精品的收率为69％，纯度96.4％，且单个杂质不大于1％。
实施例3
一种青蒿素分离纯化工艺，包括以下步骤：
S1.将青蒿石油醚提取液在常压、温度为70℃条件下浓缩至原体积的1/50，然后边搅拌边自然降温至25℃并继续保温搅拌1h后压滤，得到青蒿素粗晶1、母液1，所述母液1经过减压浓缩至干得到青蒿素浸膏1，其中所述青蒿石油醚提取液中青蒿素的含量为0.5％；
S2.将所述青蒿素浸膏1加入醇水溶液中加热至25℃，搅拌溶散1h，然后降温至40℃，离心分离，得到醇水提取液1和青蒿素浸膏2，其中，醇水溶液为体积分数为10％的叔丁醇溶液，青蒿素浸膏1与醇水溶液的质量体积比为4；
S3.将所述青蒿素浸膏2使用S2一次后得到和醇水提取液2和青蒿素浸膏3；所述青蒿素浸膏3重复步骤S2一次后得青蒿素浸膏和醇水提取液N，所述醇水提取液N用于下一批步骤S2中溶散所述青蒿素浸膏1；
S4.将所述醇水提取液1和所述醇水提取液2合并后搅拌降温至10℃并在该温度下结晶1.5h，压滤，得到青蒿素粗结晶2、母液2；
S5.将所述青蒿素粗晶1、青蒿素粗晶2合并后与醇类溶剂混合后于50℃加热搅拌溶解，随后夹套制冷至0℃，再进行填料(活性炭)吸附过滤、滤袋精滤；将精滤后的滤液加热至60℃后减压浓缩，浓缩后液体与浓缩前粗晶混合物的体积质量比为20L/kg，再梯度降温冷却至5℃，压滤，压滤后所得固体于50℃采用双锥烘干机烘干3h后得到青蒿素精品；
梯度降温过程如下：首先自然降温至室温并继续搅拌1h；随后在1h内降温至15℃并继续搅拌1h；随后在1h内降温至0℃并继续搅拌2h，梯度降温时的搅拌速度为30rad/min；
所述醇类溶剂为异丙醇，醇类溶剂与粗晶混合物的质量体积比为50L/kg。
本实施例中，青蒿素精品的收率为74％，纯度为98.7％，且单个杂质不大于1％。
实施例4
一种青蒿素分离纯化工艺，其与实施例1的区别在于，
步骤S5的操作为：将所述青蒿素粗晶1、青蒿素粗晶2合并后与醇类溶剂混合后于30℃加热搅拌溶解，随后夹套制冷至0℃，再进行填料(硅藻土)吸附过滤、滤袋精滤；将精滤后的滤液加热至40℃后减压浓缩，浓缩后液体与浓缩前粗晶混合物的体积质量比为5L/kg，
再自然冷却至0℃，压滤，压滤后所得固体于50℃采用双锥烘干机烘干3h后得到青蒿素精品；其中所述醇类溶剂为叔丁醇，醇类溶剂与粗晶混合物的质量体积比为20L/kg。
本实施例中，青蒿素精品的收率为65％，纯度为93％，且单个杂质不大于2％。
实施例5
一种青蒿素分离纯化工艺，其与实施例1的区别在于，
步骤S5中梯度降温时的搅拌速度为50rad/min。
本实施例中，青蒿素精品的收率为73％，纯度96.6％，且单个杂质不大于1％。
实施例6
一种青蒿素分离纯化工艺，其与实施例1的区别在于，
步骤S5中梯度降温过程如下：首先自然降温至室温并继续搅拌1h；随后在5h内降温至15℃并继续搅拌1h；随后在5h内降温至0℃并继续搅拌2h。
本实施例中，青蒿素精品的收率为71％，纯度96％，且单个杂质不大于1％。
以上描述了本发明的基本原理和具体实施方式，但是本发明不受上述实施例的限制，在不脱离本实用新型宗旨的前提下，本行业技术人员可以对其进行各种变化和改进，这些变化和改进均落入本发明要保护的范围内。

Claims (10)

  1. 一种青蒿素的分离纯化工艺，其特征在于，包括以下步骤：
    S1.将青蒿石油醚提取液浓缩至原体积的1/10-1/50后压滤，得到青蒿素粗晶1、母液1，所述母液1减压浓缩后得到青蒿素浸膏1，其中，所述青蒿石油醚提取液中青蒿素的含量为0.1％-1％；
    S2.将所述青蒿素浸膏1加入醇水溶液中搅拌溶散后压滤或者离心分离，得到醇水提取液1和青蒿素浸膏2；
    S3.将所述青蒿素浸膏2重复步骤S2一次后得醇水提取液2和青蒿素浸膏3；
    S4.将醇水提取液1和2合并后降温、结晶、压滤，得青蒿素粗结晶2、母液2；
    S5.将所述青蒿素粗晶1、青蒿素粗晶2合并后采用醇类溶剂溶解，过滤，将所得滤液升温至40-70℃后减压浓缩，浓缩后液体与浓缩前粗晶混合物的体积质量比为5-20L/kg，冷却、压滤、干燥得青蒿素精品；其中醇类溶剂与青蒿素粗晶混合物的体积质量比为20-100L/kg。
  2. 根据权利要求1所述的青蒿素分离纯化工艺，其特征在于：S2中所述醇水溶液的体积分数为10-50％，醇为甲醇、乙醇、正丙醇、异丙醇、正丁醇或叔丁醇。
  3. 根据权利要求1所述的青蒿素分离纯化工艺，其特征在于：S1所述中青蒿石油醚提取液中青蒿素的含量为0.1％-0.5％。
  4. 根据权利要求1所述的青蒿素分离纯化工艺，其特征在于：S5中所述醇类溶剂为甲醇、乙醇、正丙醇、异丙醇、正丁醇或叔丁醇。
  5. 根据权利要求1所述的青蒿素分离纯化工艺，S2中所述醇水溶液与青蒿素浸膏1的体积质量比为4-6:1。
  6. 根据权利要求1所述的青蒿素分离纯化工艺，其特征在于：S5所述冷却为梯度降温冷却，具体操作为：先自然降温至室温并继续保温搅拌40-70min；随后在1-2h内降温至15-20℃并继续保温搅拌40-70min；最后在1-2h内降温至0-10℃并继续保温搅拌1.5-3h。
  7. 根据权利要求6所述的青蒿素分离纯化工艺，其特征在于：所述梯度降温冷却过程中搅拌速度为10-30rad/min。
  8. 根据权利要求1所述的青蒿素分离纯化工艺，步骤S1压滤之前进行如下操作：浓缩后的溶液边搅拌边自然降温至25-35℃并继续保温搅拌1-2h。
  9. 根据权利要求1所述的青蒿素分离纯化工艺，步骤S2压滤前进行如下操作：将所述青蒿素浸膏1加入醇水溶液中加热至25-80℃，搅拌溶散1-2h，然后降温至15-40℃。
  10. 根据权利要求1所述的青蒿素分离纯化工艺，步骤S4所述的降温、结晶的具体操作为：降温至-5至10℃，结晶1-2h。
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