WO2020238294A1 - 一种单流程制备双氢青蒿素原料药的方法 - Google Patents

一种单流程制备双氢青蒿素原料药的方法 Download PDF

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WO2020238294A1
WO2020238294A1 PCT/CN2020/076035 CN2020076035W WO2020238294A1 WO 2020238294 A1 WO2020238294 A1 WO 2020238294A1 CN 2020076035 W CN2020076035 W CN 2020076035W WO 2020238294 A1 WO2020238294 A1 WO 2020238294A1
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dihydroartemisinin
single process
artemisinin
preparing
bulk drug
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PCT/CN2020/076035
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French (fr)
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彭学东
张梅
赵金召
闫勇义
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张家港威胜生物医药有限公司
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Priority to US17/611,902 priority Critical patent/US20220227779A1/en
Publication of WO2020238294A1 publication Critical patent/WO2020238294A1/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
    • C07D493/20—Spiro-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • the invention belongs to the technical field of production of dihydroartemisinin raw materials, and specifically relates to a method for preparing dihydroartemisinin raw materials in a single process.
  • Dihydroartemisinin is an artemisinin derivative with the chemical name (3R, 5aS, 6R, 8aS, 9R, 12S, 12aR)-octahydro-3,6,9-trimethyl-3 , 12-oxo-12H-pyrazo[4,3-j]-1,2-benzodioxane-10(3H)-ol.
  • the molecular formula is C 15 H 24 O 5 and the molecular weight is 284.35.
  • Dihydroartemisinin is white needle-like crystals; it is odorless and has a bitter taste. It is easily soluble in chloroform, soluble in propanol, slightly soluble in methanol or ethanol, and almost insoluble in water.
  • dihydroartemisinin The melting point of dihydroartemisinin is 145-150°C, and it decomposes at the same time when melting.
  • Dihydroartemisinin is the active metabolite of artemisinin drugs.
  • Experimental results show that dihydroartemisinin has anti-malarial, anti-tumor, anti-viral and immunomodulatory effects, and its combined use with a variety of anti-tumor drugs can reduce the side effects of anti-tumor drugs. It has stronger antimalarial activity than artemisinin, and its curative effect is 4-8 times that of artemisinin.
  • dihydroartemisininin APIs must comply with the national regulations for the production of APIs, that is, dihydroartemisinin crystals not only need to meet specific purity requirements, but the crystallization environment must be strictly controlled during the crystal preparation process. In order to prevent factors such as dust and microorganisms in the environment from affecting crystal raw materials. Otherwise, even if the purity of the dihydroartemisinin crystals is sufficient, they cannot be directly used in APIs and can only be used as an intermediate of dihydroartemisinin.
  • Chinese patent application CN102304135A discloses a production method of dihydroartemisinin.
  • the method uses methanol as the reaction solvent, suspends the raw material artemisinin in methanol at low temperature, and undergoes reduction and neutralization with sodium borohydride as a reducing agent. , The crystals are filtered by static centrifugation at low temperature, and finally washed with methanol aqueous solution and dried to obtain dihydroartemisinin crystals.
  • the yield of dihydroartemisinin prepared by the process can reach over 96%, and the purity is as high as 99.6%.
  • the production process can only be used for the preparation of dihydroartemisinin intermediates, but cannot be used for the production of dihydroartemisinin bulk drugs.
  • the present invention aims to provide a single-process preparation of dihydroartemisinin that meets the production environment specifications of the bulk drug and can produce high purity and high yield dihydroartemisinin bulk drug. Method of raw material medicine.
  • the present invention provides a method for preparing dihydroartemisinin bulk medicine in a single process, which includes the following steps:
  • phase transfer catalyst and the reducing agent are sequentially added, and the artemisinin undergoes a reduction reaction
  • step S3 Adjust the pH value of the reaction system obtained in step S2 to 5-7 with acid solution, add water and stir and then separate the liquids.
  • the aqueous phase obtained from the liquid separation is extracted with the same aprotic solvent as in step S1, and finally the organic phase obtained by extraction is combined with The organic phases obtained from liquid separation are combined, washed with water, and dried;
  • the dried organic phase in S3 is separated into crystals in a three-in-one crystallization-press filtration-drying crystallization device, and then concentrated, filtered and dried to obtain a high-quality dihydroartemisinin.
  • the aprotic solvent is toluene, dichloromethane, dichloroethane or chloroform.
  • the aprotic solvent is toluene.
  • the phase transfer catalyst is benzyltriethylammonium chloride or tetrabutylammonium bromide.
  • the amount of the phase transfer catalyst is 0.3%-0.8% by weight of artemisinin.
  • the phase transfer catalyst is added in the form of an aqueous solution, and the concentration of the aqueous solution of the phase transfer catalyst is 0.01 g/mL.
  • control temperature during the reduction reaction in S2 is -20°C to 10°C.
  • the mass-volume ratio of the artemisinin to the aprotic solvent in S1 is 1:4-8 g/mL.
  • reaction temperature in S1 is -15°C to 5°C;
  • reaction temperature is -10°C to 0°C.
  • the reducing agent in S2 is sodium borohydride or potassium borohydride, and the amount of the reducing agent is 10-20% by weight of artemisinin.
  • the acid solution is used to adjust the pH of the reaction system to control the temperature to be 0-25°C. Adjust the pH value of the reaction system to 5-7 with acid solution, that is, adopt the process of acid solution neutralization and quenching.
  • the experimental results show that when the temperature exceeds 25°C, the content of by-products increases significantly, which in turn significantly reduces the yield and purity of dihydroartemisinin in the dihydroartemisinin product.
  • step S3 the operation of adjusting the pH value of the reaction system obtained in step S2 with acid solution is completed in an automatic interlocking device
  • the automatic interlocking device includes a temperature sensor, a pH sensor, a sampling controller, a stirring device,
  • the central controller and the control panel are electrically connected to the temperature sensor, the pH sensor, the sampling controller, the stirring device, the central controller and the control panel.
  • automatic control of the neutralization and quenching process can be realized, and the reaction neutralization and quenching process can be controlled in real time, which enhances safety and occupational health protection.
  • intelligent control of the neutralization quenching process can reduce the high error of manual control, ensure the mild and stable reaction, and avoid the formation of by-products caused by excessive temperature.
  • the temperature sensor can monitor the temperature in the reaction system and control the temperature of the reaction system through the central controller; the pH sensor is used to monitor the pH change in the reaction system; and the pH value is controlled at 5 through the central controller. Between -7; the injection controller is used to control the injection volume of the acid solution and adjust the injection speed in time; the stirring device is used to stir the reaction system to ensure that the entire reaction system is uniformly neutralized and quenched .
  • reaction system be a completely dissolved reaction system.
  • the above temperature is controlled at 0-5°C.
  • the desiccant used for drying in S3 is anhydrous sodium sulfate, anhydrous calcium chloride or anhydrous magnesium sulfate.
  • the acid solution in S3 is an acetic acid or hydrochloric acid solution, and the mass concentration of the acid solution is 20%-30%.
  • the acid solution in S2 is a 25% acetic acid solution.
  • step S4 is as follows: the organic phase dried in S3 is pumped into a closed crystallization-filter-press-drying three-in-one crystallization device, after concentration under reduced pressure, water is added to stir the crystallization, filtered under pressure, and finally vacuum dried, namely Get the dihydroartemisinin fine product.
  • the temperature of the reduced pressure concentration is 50-60°C.
  • the amount of water added is 4-5 times the crystal mass; the crystallization temperature is 0-10°C.
  • the pressure of the filter press is 4-6 kg, and the filter press time is 20-50 min.
  • the temperature of vacuum drying is 50-60°C, and the time is 3-4 hours.
  • the method of adding water to the liquid and then extracting can better remove the inorganic salt produced by the reducing agent sodium borohydride and the like compared to the operation of washing with methanol and water.
  • the present invention has the following beneficial effects:
  • the method for preparing dihydroartemisinin bulk drug in a single process provided by the present invention can control the crystallization and purification process under dust-free and sterile conditions, and meet the requirements of national regulations for the production of bulk drugs; moreover, The purity and yield of the obtained dihydroartemisinin bulk drug can be as high as 99% or more, which meets the purity requirements of the bulk drug.
  • the crude dihydroartemisinin crystals are usually obtained by suction filtration after the reaction is completed, and after the methanol is completely removed by drying, the crude crystals are dissolved in a soluble solvent to perform crystal purification operations ,
  • the operation is complicated.
  • the present invention directly uses artemisinin easily dissolvable aprotic solvent as the reaction solvent and extraction solvent, so that the organic phase obtained after extraction is directly pumped into the closed crystallization-press filtration-drying three-in-one crystal
  • the device completes the operations of crystallization, pressure filtration, and drying, which meets the production environment requirements for the precipitation and purification of the crystals of the bulk drug under closed conditions. Moreover, only a single process is required, which eliminates the need for intermediate preparation of crude dihydroartemisinin and drying steps, and the process is simpler.
  • the aprotic solvent of the present invention can be recycled for the above-mentioned preparation process of dihydroartemisinin after being recovered, while the recovered methanol cannot be recycled.
  • raw materials of the same quality are provided by the present invention
  • the reaction system reduces the consumption of organic solvents and reduces environmental pollution.
  • the present invention will be further described below, and examples of the present invention will be given.
  • the crystallization-press filter-drying three-in-one crystallization equipment used in each implementation of the present invention was purchased from Jiangsu Xingke Pharmaceutical Equipment Manufacturing Co., Ltd., and the model is XKJ-1200.
  • a method for preparing dihydroartemisinin bulk drug in a single process which comprises the following steps:
  • step S3 Adjust the pH value of the reaction system obtained in step S2 to 7 with an acetic acid solution with a mass concentration of 25%, and control the temperature of the system to 0-5°C during the adjustment process; this process is completed in an automatic interlocking device, the automatic interlocking
  • the device includes a temperature sensor, a pH sensor, a sampling controller, a stirring device, a central controller, and a control panel.
  • the temperature sensor, pH sensor, a sampling controller, a stirring device, the central controller and the control panel are electrically connected
  • the temperature sensor can monitor the temperature in the reaction system and control the temperature at 0-5 °C through the central controller;
  • the pH sensor is used to monitor the pH change in the reaction system; and the pH value is controlled by the central controller Around 7;
  • the injection controller is used to control the injection volume of the acid solution and adjust the injection speed in time;
  • the stirring device is used to stir the reaction system to ensure that the entire reaction system is uniformly neutralized and quenched;
  • the purity of the refined dihydroartemisinin was 99.8%, the yield was 99.6%, and 750L of toluene was recovered.
  • a method for preparing dihydroartemisinin bulk drug in a single process which comprises the following steps:
  • step S3 Adjust the pH value of the reaction system obtained in step S2 to 7 with an acetic acid solution with a mass concentration of 25%, and control the system temperature to 0-5°C during the adjustment process; the above operation is completed with the automatic interlocking device as in Example 1; add water After stirring, the aqueous phase was separated with 200L of dichloromethane. The organic phase obtained from the extraction was combined with the separated organic phase and washed with water. Then, the washed organic phase was dried by adding sodium sulfate equivalent to 1% of its mass. Agent
  • the purity of the refined dihydroartemisinin was 99.5%, the yield was 99.3%, and 740L of methylene chloride was recovered.
  • a method for preparing dihydroartemisinin bulk drug in a single process which comprises the following steps:
  • step S3 Adjust the pH value of the reaction system obtained in step S2 to 7 with an acetic acid solution with a mass concentration of 25%, and control the temperature of the system to 30°C during the adjustment process; the above operation is completed with the automatic interlocking device as in Example 1; after adding water and stirring Liquid separation, the aqueous phase obtained by the liquid separation is extracted with 200L of toluene, the organic phase obtained from the extraction and the liquid separation organic phase are combined and washed with water, and then sodium sulfate desiccant equivalent to 1% of its mass is added to the washed organic phase;
  • the purity of the refined dihydroartemisinin was 99.1%, the yield was 99%, and 750L of toluene was recovered.
  • a method for preparing dihydroartemisinin bulk drug in a single process which comprises the following steps:
  • step S3 Adjust the pH value of the reaction system obtained in step S2 to 7 with a hydrochloric acid solution with a mass concentration of 25%, and control the temperature of the system to 0-5°C during the adjustment process; the above operation is completed with the automatic interlocking device as in Example 1; add water After stirring, the aqueous phase is separated with 200L of toluene, the organic phase obtained from the extraction is combined with the separated organic phase and washed with water, and then sodium sulfate desiccant equivalent to 1% of its mass is added to the washed organic phase;
  • the purity of the refined dihydroartemisinin was 99.3%, the yield was 99.1%, and 755L of toluene was recovered.
  • a method for preparing dihydroartemisinin bulk drug in a single process which comprises the following steps:
  • step S3 Adjust the pH value of the reaction system obtained in step S2 to 7 with an acetic acid solution with a mass concentration of 25%, and control the system temperature to 0-5°C during the adjustment process; the above operation is completed with the automatic interlocking device as in Example 1; add water After stirring, the aqueous phase is separated with 200L of toluene, the organic phase obtained from the extraction is combined with the separated organic phase and washed with water, and then sodium sulfate desiccant equivalent to 1% of its mass is added to the washed organic phase;
  • the purity of the refined dihydroartemisinin was 99.7%, the yield was 99.3%, and 755L of toluene was recovered.
  • a method for preparing dihydroartemisinin bulk drug in a single process which comprises the following steps:
  • step S3 Adjust the pH value of the reaction system obtained in step S2 to 7 with an acetic acid solution with a mass concentration of 25%, and control the system temperature to 0-5°C during the adjustment process; this process is completed in an automatic interlocking device, and water is added and stirred and then separated , The aqueous phase obtained by liquid separation is extracted with 200L of toluene, the organic phase obtained by extraction and the organic phase separated by the extraction are combined and washed with water, and then sodium sulfate desiccant equivalent to 1% of its mass is added to the washed organic phase;
  • the purity of the refined dihydroartemisinin was 99.8%, the yield was 99.4%, and 750L of toluene was recovered.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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Abstract

本发明属于双氢青蒿素原料药生产技术领域，具体涉及一种单流程制备双氢青蒿素原料药的方法。其包括如下步骤： S1.将青蒿素溶于非质子性溶剂中； S2.依次加入相转移催化剂和还原剂，青蒿素发生还原反应； S3.用酸液调节步骤S2所得反应体系的pH值至5-7，加水搅拌后分液，将分液所得水相采用与步骤S1相同的非质子性溶剂萃取，最后将萃取所得有机相与分液所得有机相合并、水洗、干燥； S4.将S3中干燥后的有机相在结晶-压滤-干燥三合一结晶装置中析出晶体后浓缩、压滤、干燥，即得双氢青蒿素精品。本发明提供了一种制备高纯度双氢青蒿素原料药的方法，该方法制得的双氢青蒿素的纯度和收率均可以高达99％以上。

Description

一种单流程制备双氢青蒿素原料药的方法 技术领域
本发明属于双氢青蒿素原料药生产技术领域，具体涉及一种单流程制备双氢青蒿素原料药的方法。
背景技术
双氢青蒿素(Dihydroartemisinin)是一种青蒿素衍生物，化学名为(3R，5aS，6R，8aS，9R，12S，12aR)-八氢-3，6，9-三甲基-3，12-桥氧-12H-吡哺并[4，3-j]-1，2-苯并二氧七环-10(3H)-醇。分子式为C 15H 24O 5，分子量是284.35。双氢青蒿素为白色针状结晶；无臭，味苦。在三氯甲烷中易溶，在丙醇中溶解，在甲醇或乙醇中略溶，在水中几乎不溶。双氢青蒿素的熔点为145-150℃，熔融时同时分解。双氢青蒿素是青蒿素类药物的活性代谢物。实验结果表明，双氢青蒿素具有抗疟、抗肿瘤、抗病毒及免疫调节等药理作用，并且与多种抗肿瘤药物联合使用可以降低抗肿瘤药物的副作用。其具有较青蒿素更强的抗疟活性，其疗效为青蒿素的4-8倍。
我国关于双氢青蒿素(DHA)制备方面的研究一直处于国际前列。如在早期，韦国锋等人(《双氢青蒿素的制备及其含量测定》[J].右江民族医学院学报,2001,(5):691-692)即发现，在乙醇溶剂中，通过硼氢化钾与青蒿素反应2h后，再盐析1.5h可得双氢青蒿素粗产物。但此方法所耗时间较长且乙醇溶剂中反应不彻底，收率较低，不利于工业生产。
现有技术中，多是采用极性质子性溶剂甲醇等作为反应溶剂，但由于原料青蒿素和产物双氢青蒿素均难溶于这类溶剂，一方面晶体析出后进行纯化时不仅需要耗费大量的有机溶剂进行洗涤；另一方面，由于原料青蒿素难溶于甲醇，反应体系只能由人工控制，不利于自动化操作，不适于工业化大规模生产。
而且，双氢青蒿素原料药的生产必须符合国家规定的原料药生产环境规范，即双氢青蒿素晶体不仅需要满足特定的纯度要求，在晶体的制备过程中还需要严格控制结晶环境，以防止如环境中的灰尘、微生物等因素影响晶体原料药。否则，即使双氢青蒿素晶体的纯度足够，也仍无法直接用于原料药，只能用作双氢青蒿素中间体。
如中国专利申请CN102304135A公开了一种双氢青蒿素的生产方法，该方法以甲醇为反应溶剂，将原料青蒿素低温悬浮于甲醇中，以硼氢化钠为还原剂经历了还原、中和、低温静 止离心过滤结晶，最后用甲醇水溶液洗涤晶体并干燥后制得双氢青蒿素晶体。该工艺制得的双氢青蒿素的收率可达96％以上，纯度高达99.6％。
但该生产工艺中中和后以真空过滤的方式得到晶体，然后采用甲醇水溶液洗涤晶体，上述两步操作只能在普通的实验环境下完成，无法实现无尘无菌操作(控制环境中的粉尘、微生物等参数)，即无法满足原料药生产规定的环境要求。
所以，该生产工艺只能用于双氢青蒿素的中间体的制备，但无法用于双氢青蒿素原料药的生产。
发明内容
为了解决现有技术中的上述问题，本发明旨在提供一种满足原料药的生产环境规范、可以制得高纯度、高收率的双氢青蒿素原料药的单流程制备双氢青蒿素原料药的方法。
为解决上述问题，本发明提供了一种单流程制备双氢青蒿素原料药的方法，其包括如下步骤：
S1.将青蒿素溶于非质子性溶剂中；
S2.依次加入相转移催化剂和还原剂，青蒿素发生还原反应；
S3.用酸液调节步骤S2所得反应体系的pH值至5-7，加水搅拌后分液，将分液所得水相采用与步骤S1相同的非质子性溶剂萃取，最后将萃取所得有机相与分液所得有机相合并、水洗、干燥；
S4.将S3中干燥后的有机相在结晶-压滤-干燥三合一结晶装置中析出晶体后浓缩、压滤、干燥，即得双氢青蒿素精品。
优选地，所述非质子性溶剂为甲苯、二氯甲烷、二氯乙烷或三氯甲烷。
进一步优选地，所述非质子性溶剂为甲苯。
优选地，所述相转移催化剂为苄基三乙基氯化铵或四丁基溴化铵。
优选地，所述相转移催化剂的用量为青蒿素重量的0.3％-0.8％。
优选地，所述相转移催化剂以水溶液的形式加入，所述相转移催化剂的水溶液的浓度为0.01g/mL。
优选地，S2中还原反应过程中控制温度为-20℃至10℃。
优选地，S1中所述青蒿素与非质子性溶剂的质量体积比为1:4-8g/mL。
优选地，S1中反应温度为-15℃至5℃；
进一步优选地，所述反应温度为-10℃至0℃。
优选地，S2中所述还原剂为硼氢化钠或硼氢化钾，还原剂的用量为青蒿素重量的10％-20％。
优选地，S3中用酸液调节反应体系的pH值时控制温度为0-25℃。用酸液调节反应体系的pH值至5-7即采用酸液中和淬灭的过程。实验结果表明，当该温度超过25℃时，副产物的含量明显增加，进而使得双氢青蒿素精品中双氢青蒿素的收率及纯度均明显降低。
当上述温度低于0℃时，中和淬灭反应进程减慢，延长了工艺周期。
优选地，步骤S3中用酸液调节步骤S2所得反应体系的pH值的操作是在自动联锁装置中完成，所述自动联锁装置包括温度传感器、pH传感器、进样控制器、搅拌装置、中央控制器和控制面板，所述温度传感器、pH传感器、进样控制器、搅拌装置、中央控制器和控制面板之间通过电联接。在该自动联锁装置中可以实现自动控制中和淬灭过程，而且可以实时控制反应中和淬灭进程，加强了安全性和职业健康保护。同时，智能控制中和淬灭过程，可以减少人工控制的高误差性，保证反应的温和平稳性，避免温度过高导致的副产物的生成。
所述温度传感器可以监测反应体系中的温度并通过中央控制器对反应体系的温度进行控制；所述pH传感器用于监测反应体系中的pH值变化；并通过中央控制器将pH值控制在5-7之间；所述进样控制器用于控制酸液的进样量，及时调整进样速度；所述搅拌装置用于对反应体系进行搅拌，使保证整个反应体系均匀发生中和淬灭反应。
采用该自动联锁装置控制所述中和淬灭过程，要求反应体系为完全溶解的反应体系。
进一步优选地，上述温度控制在0-5℃。
优选地，S3中干燥采用的干燥剂为无水硫酸钠、无水氯化钙或无水硫酸镁。
优选地，S3中酸液为醋酸或盐酸溶液，酸液的质量浓度为20％-30％。
进一步优选地，S2中酸液为25％的醋酸溶液。
优选地，步骤S4操作如下：将S3中干燥后的有机相抽入密闭的结晶-压滤-干燥三合一结晶装置中，减压浓缩之后，加水搅拌结晶，压滤，最后真空干燥，即得双氢青蒿素精品。
进一步优选地，所述减压浓缩的温度为50-60℃。
进一步优选地，加水的量为晶体质量的4-5倍；结晶温度为0-10℃。
进一步优选地，压滤的压力为4-6kg，压滤时间为20-50min。
进一步优选地，真空干燥的温度为50-60℃，时间为3-4小时。
本发明中以加水分液后再萃取的方法，相比采用甲醇水冲洗等操作，可以更好的除去还原剂硼氢化钠等产生的无机盐。
与现有技术相比，本发明具有如下有益效果：
(1)本发明提供的单流程制备双氢青蒿素原料药的方法可以将结晶及纯化过程控制在无尘无菌条件下进行，符合国家规定的原料药生产环境规范的要求；而且，制得的双氢青蒿素原料药的纯度和收率均可以高达99％以上，符合原料药的纯度要求。
(2)现有技术以甲醇作反应溶剂时，多是在反应结束后抽滤得到双氢青蒿素粗晶，干燥完全除去甲醇后再将该粗晶溶解于易溶溶剂，进行晶体纯化操作，操作复杂。而本发明则是直接采用青蒿素易于溶解的非质子性溶剂作反应溶剂和萃取溶剂，便于萃取后得到的有机相直接以管道等形式抽入密闭的结晶-压滤-干燥三合一结晶装置中完成结晶、压滤、干燥的操作，即满足了原料药的晶体的析出及纯化在密闭条件下进行的生产环境要求。而且只需要单流程，省去了中间制备双氢青蒿素粗品和干燥环节，工艺更简单。
(3)由于本发明中原料青蒿素可以较好的溶解于反应溶剂，从而降低了晶体纯化阶段的分离难度，无需大量的有机溶剂对晶体进行分离，从整个反应体系上减少了有机溶剂的用量；而且本发明采用易于回收利用的非质子性溶剂作为反应和萃取溶剂，降低了溶剂的回收难度。
本发明所述的非质子性溶剂回收后可循环用于上述双氢青蒿素的制备过程，而回收的甲醇则无法循环使用，对于该制备过程而言，相同质量的原料，采用本发明提供的反应体系减少了有机溶剂的消耗量，降低了对环境的污染。
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。本发明中各实施所用到的结晶-压滤-干燥三合一结晶设备，购于江苏兴科制药设备制造有限公司，型号是XKJ-1200。
实施例1
一种单流程制备双氢青蒿素原料药的方法，其包括如下步骤：
S1.将100kg青蒿素溶于600L甲苯中；
S2.加入含有0.5kg苄基三乙基氯化铵的水溶液50L，降温至-10℃，氮气保护下开始分批加入硼氢化钠还原剂，共16kg，控制温度不超过0℃，加完后继续反应5小时，用薄层层析法监控，当青蒿素斑点完全消失时视为反应完成；
S3.用质量浓度为25％的醋酸溶液调节步骤S2所得反应体系的pH值至7，调节过程中控制体系温度为0-5℃；该过程在自动联锁装置中完成，所述自动联锁装置包括温度传感器、pH传感器、进样控制器、搅拌装置、中央控制器和控制面板，所述温度传感器、pH传感器、进样控制器、搅拌装置、中央控制器和控制面板之间通过电联接；所述温度传感器可以监测反 应体系中的温度并通过中央控制器将温度控制在0-5℃；所述pH传感器用于监测反应体系中的pH值变化；并通过中央控制器将pH值控制在7左右；所述进样控制器用于控制酸液的进样量，及时调整进样速度；所述搅拌装置用于对反应体系进行搅拌，使保证整个反应体系均匀发生中和淬灭反应；
加水搅拌后分液，将分液所得水相采用200L甲苯萃取，萃取所得有机相与分液有机相合并后水洗，然后向水洗后的有机相中加入相当于其质量1％的硫酸钠干燥剂；
S4.将S3中干燥后的有机相抽入结晶-压滤-干燥三合一结晶装置中，在50℃条件下减压浓缩至无溶剂排出后，加入相当于晶体质量5倍的水搅拌，在0℃结晶，压滤，压滤的压力为5kg，压滤时间为30min；最后于60℃真空干燥3小时，即得双氢青蒿素精品。
本实施例中，双氢青蒿素精品的纯度为99.8％，收率为99.6％，回收甲苯750L。
实施例2
一种单流程制备双氢青蒿素原料药的方法，其包括如下步骤：
S1.将100kg青蒿素溶于600L二氯甲烷中；
S2.加入含有0.5kg苄基三乙基氯化铵的水溶液50L，降温至-10℃，氮气保护下开始分批加入硼氢化钠还原剂，共16kg，控制温度不超过0℃，加完后继续反应5小时，用薄层层析法监控，当青蒿素斑点完全消失时视为反应完成；
S3.用质量浓度为25％的醋酸溶液调节步骤S2所得反应体系的pH值至7，调节过程中控制体系温度为0-5℃；如上操作采用同实施例1的自动联锁装置完成；加水搅拌后分液，将分液所得水相采用200L二氯甲烷萃取，萃取所得有机相与分液有机相合并后水洗，然后向水洗后的有机相中加入相当于其质量1％的硫酸钠干燥剂；
S4.将S3中干燥后的有机相抽入结晶-压滤-干燥三合一结晶装置中，在50℃条件下减压浓缩至无溶剂排出后，加入相当于晶体质量5倍的水搅拌，在0℃结晶，压滤，压滤的压力为5kg，压滤时间为30min；最后于60℃真空干燥3小时，即得双氢青蒿素精品。
本实施例中，双氢青蒿素精品的纯度为99.5％，收率为99.3％，回收二氯甲烷740L。
实施例3
一种单流程制备双氢青蒿素原料药的方法，其包括如下步骤：
S1.将100kg青蒿素溶于600L甲苯中；
S2.加入含有0.5kg苄基三乙基氯化铵的水溶液50L，降温至-10℃，氮气保护下开始分批加入硼氢化钠还原剂，共16kg，控制温度不超过0℃，加完后继续反应5小时，用薄层层析法监控，当青蒿素斑点完全消失时视为反应完成；
S3.用质量浓度为25％的醋酸溶液调节步骤S2所得反应体系的pH值至7，调节过程中控制体系温度为30℃；如上操作采用同实施例1的自动联锁装置完成；加水搅拌后分液，将分液所得水相采用200L甲苯萃取，萃取所得有机相与分液有机相合并后水洗，然后向水洗后的有机相中加入相当于其质量1％的硫酸钠干燥剂；
S4.将S3中干燥后的有机相抽入结晶-压滤-干燥三合一结晶装置中，在50℃条件下减压浓缩至无溶剂排出后，加入相当于晶体质量5倍的水搅拌，在0℃结晶，压滤，压滤的压力为5kg，压滤时间为30min；最后于60℃真空干燥3小时，即得双氢青蒿素精品。
本实施例中，双氢青蒿素精品的纯度为99.1％，收率为99％，回收甲苯750L。
实施例4
一种单流程制备双氢青蒿素原料药的方法，其包括如下步骤：
S1.将100kg青蒿素溶于600L甲苯中；
S2.加入含有0.5kg苄基三乙基氯化铵的水溶液50L，降温至-10℃，氮气保护下开始分批加入硼氢化钠还原剂，共16kg，控制温度不超过0℃，加完后继续反应5小时，用薄层层析法监控，当青蒿素斑点完全消失时视为反应完成；
S3.用质量浓度为25％的盐酸溶液调节步骤S2所得反应体系的pH值至7，调节过程中控制体系温度为0-5℃；如上操作采用同实施例1的自动联锁装置完成；加水搅拌后分液，将分液所得水相采用200L甲苯萃取，萃取所得有机相与分液有机相合并后水洗，然后向水洗后的有机相中加入相当于其质量1％的硫酸钠干燥剂；
S4.将S3中干燥后的有机相抽入结晶-压滤-干燥三合一结晶装置中，在50℃条件下减压浓缩至无溶剂排出后，加入相当于晶体质量5倍的水搅拌，在0℃结晶，压滤，压滤的压力为5kg，压滤时间为30min；最后于60℃真空干燥3小时，即得双氢青蒿素精品。
本实施例中，双氢青蒿素精品的纯度为99.3％，收率为99.1％，回收甲苯755L。
实施例5
一种单流程制备双氢青蒿素原料药的方法，其包括如下步骤：
S1.将100kg青蒿素溶于600L甲苯中；
S2.加入含有2kg苄基三乙基氯化铵的水溶液50L，降温至-10℃，氮气保护下开始分批加入硼氢化钠还原剂，共16kg，控制温度不超过0℃，加完后继续反应5小时，用薄层层析法监控，当青蒿素斑点完全消失时视为反应完成；
S3.用质量浓度为25％的醋酸溶液调节步骤S2所得反应体系的pH值至7，调节过程中控制体系温度为0-5℃；如上操作采用同实施例1的自动联锁装置完成；加水搅拌后分液，将分液 所得水相采用200L甲苯萃取，萃取所得有机相与分液有机相合并后水洗，然后向水洗后的有机相中加入相当于其质量1％的硫酸钠干燥剂；
S4.将S3中干燥后的有机相抽入结晶-压滤-干燥三合一结晶装置中，在50℃条件下减压浓缩至无溶剂排出后，加入相当于晶体质量5倍的水搅拌，在0℃结晶，压滤，压滤的压力为5kg，压滤时间为30min；最后于60℃真空干燥3小时，即得双氢青蒿素精品。
本实施例中，双氢青蒿素精品的纯度为99.7％，收率为99.3％，回收甲苯755L。
实施例6
一种单流程制备双氢青蒿素原料药的方法，其包括如下步骤：
S1.将100kg青蒿素溶于600L甲苯中；
S2.加入含有0.5kg苄基三乙基氯化铵的水溶液50L，降温至-10℃，氮气保护下开始分批加入硼氢化钠还原剂，共16kg，控制温度不超过0℃，加完后继续反应5小时，用薄层层析法监控，当青蒿素斑点完全消失时视为反应完成；
S3.用质量浓度为25％的醋酸溶液调节步骤S2所得反应体系的pH值至7，调节过程中控制体系温度为0-5℃；该过程在自动联锁装置中完成，加水搅拌后分液，将分液所得水相采用200L甲苯萃取，萃取所得有机相与分液有机相合并后水洗，然后向水洗后的有机相中加入相当于其质量1％的硫酸钠干燥剂；
S4.将S3中干燥后的有机相抽入结晶-压滤-干燥三合一结晶装置中，在50℃条件下减压浓缩至无溶剂排出后，加入相当于晶体质量5倍的水搅拌，在0℃结晶，压滤，压滤的压力为8kg，压滤时间为30min；最后于60℃真空干燥3小时，即得双氢青蒿素精品。
本实施例中，双氢青蒿素精品的纯度为99.8％，收率为99.4％，回收甲苯750L。
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. 一种单流程制备双氢青蒿素原料药的方法，其包括如下步骤：
    S1.将青蒿素溶于非质子性溶剂中；
    S2.依次加入相转移催化剂和还原剂，青蒿素发生还原反应；
    S3.用酸液调节步骤S2所得反应体系的pH值至5-7，加水搅拌后分液，将分液所得水相采用与步骤S1相同的非质子性溶剂萃取，最后将萃取所得有机相与分液所得有机相合并、水洗、干燥；
    S4.将S3中干燥后的有机相在结晶-压滤-干燥三合一结晶装置中析出晶体后浓缩、压滤、干燥，即得双氢青蒿素精品。
  2. 根据权利要求1所述的单流程制备双氢青蒿素原料药的方法，所述非质子性溶剂为甲苯、二氯甲烷、二氯乙烷或三氯甲烷。
  3. 根据权利要求1所述的单流程制备双氢青蒿素原料药的方法，步骤S3中所述压滤的压力为4-6kg，压滤时间为20-50min。
  4. 根据权利要求1所述的单流程制备双氢青蒿素原料药的方法，S3中用酸液调节反应体系的pH值时控制温度为0-25℃。
  5. 根据权利要求1所述的单流程制备双氢青蒿素原料药的方法，S3中酸液为醋酸或盐酸溶液，酸液的质量浓度为20％-30％。
  6. 根据权利要求5所述的单流程制备双氢青蒿素原料药的方法，S3中酸液为质量浓度为25％的醋酸溶液。
  7. 根据权利要求1所述的单流程制备双氢青蒿素原料药的方法，所述相转移催化剂为苄基三乙基氯化铵或四丁基溴化铵。
  8. 根据权利要求1所述的单流程制备双氢青蒿素原料药的方法，所述相转移催化剂的用量为青蒿素重量的0.3％-0.8％。
  9. 根据权利要求1所述的单流程制备双氢青蒿素原料药的方法，S1中所述青蒿素与非质子性溶剂的质量体积比为1:4-8g/mL。
  10. 根据权利要求1所述的单流程制备双氢青蒿素原料药的方法，S2中所述还原剂为硼氢化钠或硼氢化钾，还原剂的用量为青蒿素重量的10％-20％。
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