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A new method for large-scale extraction of ephedra alkaloids
CN1600777A
China
Description
translated from Chinese
技术领域technical field
本发明涉及一种大规模提取麻黄生物碱包括麻黄碱、伪麻黄碱、甲基麻黄碱、去甲基伪麻黄碱等的生产方法。The invention relates to a production method for large-scale extraction of ephedra alkaloids including ephedrine, pseudoephedrine, methylephedrine, demethylpseudoephedrine and the like.
背景技术Background technique
麻黄作为传统中药材，至今已有四千多年的应用历史。药用种类主要是草麻黄，木贼麻黄和中麻黄。主要有发汗、平喘、利水、除风作用。可治风寒感冒、发热恶寒、无汗、百日咳、支气管炎、支气管哮喘等疾病。其主要有效成分为(-)麻黄碱和(+)伪麻黄碱两种含氮甲基类生物碱，其结构与肾上腺素结构类似。由于含PPA的药物被国内外暂停使用后，麻黄碱作为PPA的最佳替代品，仅国内市场需求量就净增200余吨，同时国际市场年需求量也发展到1600吨。目前实验室和医院常规提取麻黄碱多采用酸水煮提法，但提取时间长，提取率低，而在目前企业采用的麻黄碱生产工艺中，多是用热水进行多次热压逆流浸煮，能耗较大，且时间较长。。As a traditional Chinese medicine, ephedra has a history of more than 4,000 years of application. The medicinal species are mainly grass ephedra, horsetail ephedra and middle ephedra. It mainly has the effects of sweating, relieving asthma, diuresis, and removing wind. It can cure wind-cold cold, fever and chills, no sweat, whooping cough, bronchitis, bronchial asthma and other diseases. Its main active ingredients are (-) ephedrine and (+) pseudoephedrine, two nitrogen-containing methyl alkaloids, whose structure is similar to that of epinephrine. Since the use of PPA-containing drugs has been suspended at home and abroad, ephedrine, as the best substitute for PPA, has a net increase of more than 200 tons in the domestic market alone, and the annual demand in the international market has also grown to 1,600 tons. At present, the routine extraction of ephedrine in laboratories and hospitals mostly adopts the extraction method of acid water boiling, but the extraction time is long and the extraction rate is low. Cooking consumes a lot of energy and takes a long time. .
目前企业采用的麻黄碱生产工艺用甲苯或二甲苯进行溶剂萃取，毒性较高且溶剂损失偏大。由于采用多次精制、脱色、结晶，才可得到纯品，使得生产周期长，工艺复杂，环境污染严重且能耗较大。The ephedrine production process currently adopted by enterprises uses toluene or xylene for solvent extraction, which has high toxicity and large solvent loss. Due to multiple refining, decolorization and crystallization, the pure product can be obtained, resulting in long production cycle, complex process, serious environmental pollution and high energy consumption.
另外，CN1201029A公开了一种利用大孔树脂制备麻黄精粉及副产品鞣质的生产新工艺。该方法是在现有麻黄粉提取工艺基础上，加设一道浸提液过大孔树脂床的工序，使得副产品鞣质被吸附得到富集，而其它物质，包括麻黄碱，均透过树脂，未被吸附。由于该工艺只将麻黄粉中的鞣质分离出来，对其它杂质并未有明显的分离作用。因此，麻黄碱的含量仅从≤4％提高到6～10％，有效成分含量仍然很低，属于麻黄粗粉。可见，这类方法也存在着一定缺陷。In addition, CN1201029A discloses a new production process for preparing ephedra powder and by-product tannin by using macroporous resin. The method is based on the existing ephedra powder extraction process, adding a process of extracting liquid through the macroporous resin bed, so that the by-product tannin is absorbed and enriched, while other substances, including ephedrine, are all penetrated through the resin, not adsorbed. Because this process only separates the tannins in the ephedra powder, it does not have a significant separation effect on other impurities. Therefore, the content of ephedrine is only increased from ≤4% to 6-10%, and the active ingredient content is still very low, which belongs to ephedra meal. It can be seen that this method also has certain defects.
发明内容Contents of the invention
本发明的目的是克服现有技术存在的缺点，通过利用大孔树脂吸附游离态麻黄碱的性质，提供从麻黄碱提取液中快速、高效地提取麻黄碱的生成新工艺，即提供一种可以部分取代现有生产工艺和CN1201029A工艺的简便易行、高效、快速、成本低并减少环境污染的新方法。The purpose of the present invention is to overcome the shortcoming that prior art exists, by utilizing the character of macroporous resin adsorption free state ephedrine, provide the generation new technology that extracts ephedrine from ephedrine extraction solution rapidly, efficiently, promptly provide a kind of can partly The invention is a new method which replaces the existing production technology and the CN1201029A technology, which is simple, efficient, fast, low in cost and reduces environmental pollution.
本发明的目的可通过如下措施来实现：The purpose of the present invention can be achieved through the following measures:
一种大规模提取麻黄生物碱包括麻黄碱、伪麻黄碱、甲基麻黄碱、去甲基伪麻黄碱等的生产方法，其特征在于按以下步骤进行：A kind of large-scale extraction of ephedra alkaloids comprises the production method of ephedrine, pseudoephedrine, methylephedrine, demethylpseudoephedrine etc., it is characterized in that carrying out according to the following steps:
1.用频率为20KHz，功率为50W~10000W的超声对麻黄草粉末在选自水、盐酸溶液，氢氧化钠溶液中进行超声提取。1. Be 20KHz with frequency, the ultrasonic wave that power is 50W～10000W is selected from water, hydrochloric acid solution, and carries out ultrasonic extraction in sodium hydroxide solution to ephedra powder.
在上述提取方法中，所用麻黄草为细碎形式，粒径小于等于5毫米。In the above extraction method, the herba ephedra used is in a finely divided form, with a particle size of less than or equal to 5 mm.
在上述提取方法中，所用超声时间为0.5～120分钟。In the above extraction method, the ultrasonic time used is 0.5-120 minutes.
在上述提取方法中，所述溶剂与麻黄草的量按重量比计为1∶3～30In the above-mentioned extraction method, the amount of the solvent and Ephedra is 1: 3～30 by weight
在上述提取方法中，所用盐酸溶液浓度为0.0001～1N，氢氧化钠浓度为0.0001～1N。In the above extraction method, the concentration of the hydrochloric acid solution used is 0.0001-1N, and the concentration of sodium hydroxide is 0.0001-1N.
2.将浸出液过滤后，用氢氧化钠溶液调pH为8~14，过滤后，取滤液经弱酸性阳离子交换树脂柱或大孔树脂柱，流速为0.5毫升/分钟～100毫升/分钟。2. After filtering the leachate, use sodium hydroxide solution to adjust the pH to 8~14. After filtering, take the filtrate and pass it through a weakly acidic cation exchange resin column or a macroporous resin column at a flow rate of 0.5 ml/min to 100 ml/min.
3.交换、吸附完毕，用盐酸或盐酸与有机溶剂的混合液洗脱，洗脱液经常规减压浓缩后，得盐酸麻黄碱结晶，洗脱后的树脂用有机溶剂冲洗至无色，并用蒸馏水冲洗1～20个床体积后复用。3. After exchange and adsorption, elute with hydrochloric acid or the mixed solution of hydrochloric acid and organic solvent. After the eluent is concentrated under reduced pressure, the crystallization of ephedrine hydrochloride is obtained. The resin after elution is rinsed to colorless with an organic solvent, and washed with an organic solvent. Rinse with distilled water for 1-20 bed volumes and reuse.
在上述洗脱过程中，所用盐酸浓度为0.001～1N.In the above elution process, the concentration of hydrochloric acid used is 0.001～1N.
在上述洗脱过程中，所用有机溶剂包括乙醇，甲醇，丙酮等。盐酸与有机溶剂的比例为1∶0.1～10。In the above elution process, the organic solvents used include ethanol, methanol, acetone and the like. The ratio of hydrochloric acid to organic solvent is 1:0.1～10.
下面对本发明加以详尽说明The present invention is described in detail below
1.超声技术在中草药成分提取中的应用是利用超声波的空化作用，可加速有效成分进入溶剂，增加有效成分的提取率。另外，超声波的次级效应，如机械振动，乳化，扩散，击碎，化学效应也能加速欲提取成分的扩散释放，充分与溶剂混合，促进提取的进行。微波则是利用在微波场中，吸收微波能力的差异使得中药中的某些区域或某些组分被选择性的加热，从而使有效成分从中药中分离，进入到介电常数较小、微波吸收能力相对差的溶剂中。超声技术和微波技术在中药成分提取中已有较多应用]。与常规技术相比，这两种提取技术都具有操作工艺简单，提取时间短，溶剂耗量少，有效成分提取率高的特点。1. The application of ultrasonic technology in the extraction of Chinese herbal medicine components is to use the cavitation effect of ultrasonic waves, which can accelerate the entry of active ingredients into the solvent and increase the extraction rate of active ingredients. In addition, the secondary effects of ultrasonic waves, such as mechanical vibration, emulsification, diffusion, crushing, and chemical effects can also accelerate the diffusion and release of the ingredients to be extracted, fully mix with the solvent, and promote the extraction. Microwaves are used in the microwave field. The difference in the ability to absorb microwaves makes certain areas or certain components in the traditional Chinese medicine selectively heated, so that the active ingredients are separated from the traditional Chinese medicine and enter into a microwave with a small dielectric constant. In solvents with relatively poor absorption capacity. Ultrasonic technology and microwave technology have been widely used in the extraction of traditional Chinese medicine components ] . Compared with conventional techniques, these two extraction techniques have the characteristics of simple operation process, short extraction time, less solvent consumption and high extraction rate of active ingredients.
2.麻黄碱能与盐酸结合成盐酸麻黄碱，在水中解离成阳离子状态，该状态下的麻黄碱是很难被以吸附为主要作用力的大孔树脂所截留。另一方面，大孔树脂对游离态麻黄碱的吸附效果很好，同时麻黄碱也较易被洗脱。2. Ephedrine can be combined with hydrochloric acid to become ephedrine hydrochloride, which dissociates into a cationic state in water, and the ephedrine in this state is difficult to be intercepted by the macroporous resin with adsorption as the main force. On the other hand, the adsorption effect of macroporous resin to free ephedrine is very good, and ephedrine is also more easily washed out simultaneously.
CN1201029A采用盐酸调pH5-8使麻黄碱形成盐酸盐，不被大孔树脂吸附，因此透过树脂，此流出液经浓缩干燥后得麻黄精粉纯度为6～10％。而提取液中的鞣质则被大孔树脂吸附，之后用乙醇洗脱得副产品鞣质。CN1201029A uses hydrochloric acid to adjust the pH to 5-8 to make ephedrine form hydrochloride, which is not absorbed by macroporous resin, so it permeates the resin, and the effluent is concentrated and dried to obtain ephedrine fine powder with a purity of 6-10%. The tannin in the extract is adsorbed by the macroporous resin, and then eluted with ethanol to obtain the by-product tannin.
而本发明是将麻黄草提取液中的麻黄碱用NaOH调pH8-14控制在游离态。只有此状态下的麻黄碱才能被弱酸性阳离子交换树脂和大孔树脂较好的吸附。之后，采用盐酸洗脱，使游离态麻黄碱变成盐酸麻黄碱，不被弱酸性阳离子交换树脂和大孔树脂吸附，从而从树脂上解吸。And the present invention is that the ephedrine in the Herba Ephedra extract is controlled in free state with NaOH adjusting pH8-14. Only the ephedrine in this state can be better adsorbed by weakly acidic cation exchange resin and macroporous resin. Afterwards, adopt hydrochloric acid elution, make free state ephedrine become ephedrine hydrochloride, not be adsorbed by weakly acidic cation exchange resin and macroporous resin, thereby desorb from resin.
在本发明中，麻黄草提取液上柱前，游离态麻黄碱含量约为5％，上柱后用盐酸洗脱，洗脱液减压干燥，得到纯度为80％~97％的盐酸麻黄碱结晶。麻黄碱的盐酸化和洗脱一步完成，简单快速高效。In the present invention, the content of free ephedrine in the ephedra herba extract is about 5% before it is applied to the column. After the column is applied, it is eluted with hydrochloric acid, and the eluent is dried under reduced pressure to obtain crystals of ephedrine hydrochloride with a purity of 80% to 97%. . The hydrochlorination and elution of ephedrine are completed in one step, which is simple, fast and efficient.
3.在CN1201029A中，大孔树脂吸附了鞣质，使其它杂质和盐酸麻黄碱一起透过树脂，由于未除去杂质，因此所得麻黄精粉中的麻黄碱含量较低，含量为6～10％，提高了1～2倍。3. In CN1201029A, the macroporous resin has adsorbed tannin, so that other impurities and ephedrine hydrochloride can pass through the resin together. Since the impurities are not removed, the ephedrine content in the obtained ephedra powder is relatively low, and the content is 6 to 10%. , increased by 1 to 2 times.
而在本发明中，盐酸只将麻黄碱从树脂上洗出，大部分脂溶性物质及其它杂质留在树脂上，因此盐酸麻黄碱纯度较高，达到90％以上，与处理前相比提高了15～19倍。And in the present invention, hydrochloric acid only ephedrine is washed out from resin, and most of fat-soluble matter and other impurity stay on resin, so ephedrine hydrochloride purity is higher, reaches more than 90%, compared with before processing, improves 15 to 19 times.
4.在CN1201029A中，并未提到麻黄碱的回收率是多少，而在本发明中采用的洗脱条件，回收率可达97％4. In CN1201029A, it is not mentioned how much the recovery rate of ephedrine is, and the elution condition adopted in the present invention, the recovery rate can reach 97%
5.本发明工艺简单，效率高，耗时短，成本低且环境污染小。5. The process of the present invention is simple, high in efficiency, short in time consumption, low in cost and less in environmental pollution.
下面再以实施例作进一步详述。Further details are given below with examples.
具体实施方式Detailed ways
实施例一：Embodiment one:
将25克麻黄草粉碎后，加入100毫升水，用频率为20KHz，功率为50W的超声提取30分钟，过滤除去药渣；用0.5N NaOH调节浸出液pH为9，将滤液通过南开大学化工厂生产的D151弱酸性阳离子交换树脂。交换完毕后，用0.01N盐酸进行洗脱，将洗脱液减压浓缩得盐酸麻黄碱晶体；树脂柱则用10％乙醇冲洗后可反复使用，乙醇可减压回收。采用该工艺使上样前麻黄碱的含量4.9％提高到90％以上，纯度提高了18.5倍，回收率为96％。After crushing 25 grams of Ephedra herbae, add 100 ml of water, extract it with an ultrasonic wave with a frequency of 20KHz and a power of 50W for 30 minutes, filter and remove the medicinal residues; use 0.5N NaOH to adjust the pH of the leachate to 9, and pass the filtrate through Nankai University Chemical Plant to produce D151 weakly acidic cation exchange resin. After the exchange, elute with 0.01N hydrochloric acid, and concentrate the eluate under reduced pressure to obtain ephedrine hydrochloride crystals; the resin column can be used repeatedly after being washed with 10% ethanol, and the ethanol can be recovered under reduced pressure. By adopting the technology, the content of ephedrine before sample loading is increased from 4.9% to more than 90%, the purity is increased by 18.5 times, and the recovery rate is 96%.
实施例二：Embodiment two:
将25克麻黄草粉碎后，加入100毫升0.001N盐酸溶液，用频率为20KHz，功率为50W的超声提取30分钟，过滤除去药渣；用0.5N NaOH调节浸出液pH为14，将滤液通过Rohm&Haas公司的Amberlite XAD-7大孔树脂柱。吸附完毕后，用0.01N盐酸与乙醇2∶1的混合溶液进行洗脱。将洗脱液减压浓缩得盐酸麻黄碱晶体；树脂柱则用10％乙醇冲洗后可反复使用，乙醇可减压回收。采用该工艺使上样前麻黄碱的含量5.5％提高到85％以上，纯度提高了14.8倍，回收率为97％。After crushing 25 grams of Ephedra herbae, add 100 milliliters of 0.001N hydrochloric acid solution, use a frequency of 20KHz, a power of 50W for ultrasonic extraction for 30 minutes, filter and remove the medicinal residues; use 0.5N NaOH to adjust the pH of the leachate to 14, and pass the filtrate through Rohm&Haas company Amberlite XAD-7 macroporous resin column. After the adsorption is complete, elute with a 2:1 mixed solution of 0.01N hydrochloric acid and ethanol. Concentrate the eluent under reduced pressure to obtain crystals of ephedrine hydrochloride; the resin column can be used repeatedly after being washed with 10% ethanol, and the ethanol can be recovered under reduced pressure. By adopting the technology, the content of ephedrine before sample loading is increased from 5.5% to more than 85%, the purity is increased by 14.8 times, and the recovery rate is 97%.
实施例三：Embodiment three:
将25克麻黄草粉碎后，加入100毫升0.005N氢氧化钠溶液，用频率为20KHz，功率为50W的超声提取30分钟，过滤除去药渣；用0.5N NaOH调节浸出液pH为10，将滤液通过Rohm&Haas公司的Amberlite XAD-7大孔树脂柱。交换完毕后，用0.002N盐酸与丙酮3∶1的混合液进行洗脱，将洗脱液减压浓缩得盐酸麻黄碱晶体；树脂柱则用10％乙醇冲洗后可反复使用，乙醇可减压回收。采用该工艺使上样前麻黄碱的含量4.1％提高到78％以上，纯度提高了18.9倍，回收率为95％。After crushing 25 grams of Ephedra herbae, add 100 milliliters of 0.005N sodium hydroxide solution, use ultrasonic extraction with a frequency of 20KHz and a power of 50W for 30 minutes, filter and remove the medicinal residues; use 0.5N NaOH to adjust the pH of the leachate to 10, pass the filtrate through Amberlite XAD-7 macroporous resin column from Rohm&Haas. After the exchange is completed, elute with a 3:1 mixture of 0.002N hydrochloric acid and acetone, and concentrate the eluate under reduced pressure to obtain ephedrine hydrochloride crystals; the resin column can be used repeatedly after being washed with 10% ethanol, and ethanol can be used under reduced pressure. Recycle. By adopting the technology, the content of ephedrine before sample loading is increased from 4.1% to more than 78%, the purity is increased by 18.9 times, and the recovery rate is 95%.
实施例四：Embodiment four:
将25克麻黄草粉碎后，加入100毫升0.005N氢氧化钠溶液，用功率为1200W的微波声提取30分钟，过滤除去药渣；用0.5N NaOH调节浸出液pH为10，将滤液通过Rohm&Haas公司的Amberlite XAD-7大孔树脂柱。交换完毕后，用0.002N盐酸与丙酮3∶1的混合液进行洗脱，将洗脱液减压浓缩得盐酸麻黄碱晶体；树脂柱则用10％乙醇冲洗后可反复使用，乙醇可减压回收。采用该工艺使上样前麻黄碱的含量4.1％提高到78％以上，纯度提高了18.9倍，回收率为95％。After pulverizing 25 grams of Ephedra herbae, add 100 milliliters of 0.005N sodium hydroxide solution, extract 30 minutes with the microwave sound of 1200W, filter and remove the medicinal residues; adjust the pH of the leachate to be 10 with 0.5N NaOH, pass the filtrate through a Rohm&Haas company's Amberlite XAD-7 macroporous resin column. After the exchange is completed, elute with a 3:1 mixture of 0.002N hydrochloric acid and acetone, and concentrate the eluate under reduced pressure to obtain ephedrine hydrochloride crystals; the resin column can be used repeatedly after being washed with 10% ethanol, and ethanol can be used under reduced pressure. Recycle. By adopting the technology, the content of ephedrine before sample loading is increased from 4.1% to more than 78%, the purity is increased by 18.9 times, and the recovery rate is 95%.