CN106939006B - 一种从赛北紫堇中提取分离白毛茛碱的方法 - Google Patents
一种从赛北紫堇中提取分离白毛茛碱的方法 Download PDFInfo
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Abstract
本发明公开了一种从赛北紫堇中提取分离白毛茛碱的方法，属于天然产物提取分离技术领域，该方法以罂粟科紫堇属植物赛北紫堇为原料，经过粉碎碱化、超临界CO2萃取、膜分离技术结合阳离子交换树脂和重结晶的方法实现了赛北紫堇中高纯度白毛茛碱的分离。本发明所用的方法有毒试剂用量少，产率高达0.43％，且白毛茛碱的纯度可达99.0％。
Description
技术领域
本发明涉及一种从罂粟科紫堇属植物中提取、分离白毛茛碱的方法，具体是一种从赛北紫堇中大量制取高纯度白毛茛碱的方法。
背景技术
赛北紫堇(Corydalis impatiens)为罂粟科紫堇属植物，收载于《中华本草》藏药卷，其根、茎、叶、花均可入药，具有除热消肿、活血散瘀、收敛止痒、祛风利气等功效。赛北紫堇广泛分布在青海、西藏、甘肃、四川及内蒙古等地，为藏药常用药材。本属植物主要含苄基异喹啉类、苯酚异喹啉类、苯并菲啶类、小檗碱类、阿朴菲类、普罗托品类及螺苄异喹啉类等结构类型的生物碱。
白毛茛碱(hydrastine)又称北美黄连碱，是一种苯酚异喹啉类生物碱，由阿尔弗雷德·杜兰德发现于1851年。有研究表明，白毛茛碱可以显著抑制耐甲氧西林金黄色葡萄球菌(MRSA)，有预防感染的功效；对具有多药耐药性的恶性疟原虫菌株有明显的抑制效果，且对正常细胞没有毒性；白毛茛碱可以抑制CYP2E1的活性，对对乙酰氨基酚引起的肝脏损伤起到防护作用；抑制PAK4激酶活性从而抑制下游与肿瘤增长有关的信号分子，引起肺癌细胞凋亡，起到抗肿瘤的作用。此外，白毛茛碱还有降血压、调节平滑肌和止血等功能。
目前只有从赛北紫堇中提取总生物碱的文献，而分离白毛茛碱的文献较少，且所得白毛茛碱的产率低于万分之一。如专利CN103610762(一种塞北紫堇总生物碱提取物及提取方法，申请号201310680353.6)采用碱性乙醇回流提取总生物碱，其中白毛茛碱的含量较低。由于生物碱在天然植物中的含量较低，用水提或有机溶剂提取的方法会引入其他成分，为了得到高纯度的白毛茛碱单体必须对其进行精制纯化。
发明内容
技术问题：本发明的目的在于提供一种从赛北紫堇中提取分离白毛茛碱的方法，该方法成本低、操作简单，得到的白毛茛碱产量大且纯度高达99％。
技术方案：本发明提供的一种从赛北紫堇中提取分离白毛茛碱的方法，包括以下步骤：
步骤1.粉碎、碱化：将赛北紫堇全草阴干，粉碎至40-60目，得到赛北紫堇粉末，加入Na2CO3溶液浸泡3-4小时，晾干后过40-60目筛；
步骤2.超临界提取：将处理好的赛北紫堇粉末装入超临界萃取釜中，超临界CO2萃取，用乙醇溶液为夹带剂动态提取，解析萃取液并回收乙醇，得到粗生物碱；
步骤3.微滤：将粗生物碱浸膏溶解在酸水中并调节溶液pH值至2-3，将此溶液用孔径在0.5-1.0微米的陶瓷膜进行微滤处理，控制微滤温度在25-35℃，微滤压力在0.5-0.7MPa，除去颗粒物和高分子物质；
步骤4.超滤：将微滤后的溶液用聚砜中空纤维超滤膜进行超滤处理，分子截留量在4000-8000D，控制超滤压力在0.1-0.3MPa，操作温度为25-35℃，溶液pH值维持在2-3，除去大分子物质如多糖、胶质、蛋白质及色素；
步骤5.离子交换树脂分离：将所得滤液过处理好的酸性阳离子交换树脂柱，调节上样流速，先用去离子水冲洗至中性，除去水溶性小分子杂质，再调节洗脱流速用1％Na2CO3溶液碱化50-80％乙醇洗脱，收集洗脱液用碘化铋钾显色剂检测，直至无生物碱流出为止，合并检测呈阳性的洗脱液；
步骤6.重结晶：将所得的上述洗脱液减压浓缩、干燥，加入二氯甲烷溶解过滤，然后用常规方法重结晶，过滤，得到结晶物即为白毛茛碱。
其中，
所述的步骤1中，加入的Na2CO3溶液pH值为10-11，赛北紫堇粉末与Na2CO3溶液的质量比为1:1.5-1:2。
所述的步骤2中，调节萃取温度为30～45℃，萃取压力为20～30MPa，夹带剂为90％的乙醇溶液，萃取时间为2-4小时状态为动态提取，流速为1.0-1.5mL/min。
所述的步骤3中，粗生物碱与酸水的质量比为1:20-1:40；酸水溶液为盐酸或硫酸溶液。
所述的步骤5中，所述的酸性阳离子交换树脂采用001×7聚苯乙烯磺酸型阳离子交换树脂；上样流速为1-2BV/h，洗脱流速为2-3BV/h。
有益效果：与现有技术相比，本发明的有益效果为：
(1)超临界流体萃取温度较低，生物碱不易分解，且超临界流体在高压低温时对生物碱的溶解性比传统的有机溶剂法要强，提高了提取率。
(2)膜分离技术，设备简单常温下操作，药材中的生物碱不易分解变质，采用不同孔径的膜依次过滤，大分子物质有效分离，操作过程能耗低，不消耗试剂且经过处理后的膜可重复使用。
(3)整个操作过程均在常温下进行，具有制取过程简单，收率高，所制得的白毛茛碱纯度高等特点。
附图说明
图1是利用本发明制备的高纯度白毛茛碱的色谱出峰图谱。
图2是利用本发明制备的白毛茛碱的1H-NMR图谱。
图3是利用本发明制备的白毛茛碱的13C-NMR图谱。
具体实施方式
下面对本发明技术方案进行详细说明，但是本发明的保护范围不局限于所述实施案例。
实施案例1：
首先将干燥赛北紫堇全草重约5.0kg，全草粉碎至40目，加入pH为11的Na2CO3溶液10L，浸泡4h，晾干后过40目筛。将碱化后的赛北紫堇粉末加入到萃取釜中，调节萃取温度为35℃，萃取压力为20MPa，用90％乙醇为夹带剂，调节夹带剂的流速为1.0mL/min，动态萃取2小时。萃取完成后减压回收溶剂。上述生物碱浸膏50g用1L盐酸水溶液溶解，调节pH值为2.0，控制压力为0.5MPa，温度为25℃用陶瓷微滤。收集滤液保持温度不变，用截留分子量为6000D的中空纤维超滤膜超滤，控制压力为0.3MPa。所得滤液过001×7聚苯乙烯磺酸型阳离子交换树脂，控制上样流速为1BV/h，用去离子水洗脱除去中性及酸性杂志，控制洗脱流速为2BV/h。再用1％Na2CO3溶液碱化，50％乙醇洗脱，每100mL接收一次洗脱液，薄层色谱检测，收集碘化铋钾呈阳性的洗脱液。将洗脱液浓缩，用二氯甲烷溶解，过滤，重结晶即得到白毛茛碱。
实施案例2：
首先将干燥赛北紫堇全草重约5.0kg，全草粉碎至60目，加入pH为10的Na2CO3溶液12L，浸泡4h，晾干后过60目筛。将碱化后的赛北紫堇粉末加入到萃取釜中，调节萃取温度为45℃，萃取压力为25MPa，用90％乙醇为夹带剂，调节夹带剂的流速为1.5mL/min，动态萃取4小时。萃取完成后减压回收溶剂。上述生物碱浸膏45g用1.8L硫酸水溶液溶解，调节pH值为3.0，控制压力为0.6MPa，温度为30℃用陶瓷微滤。收集滤液保持温度不变，用截留分子量为8000D的中空纤维超滤膜超滤，控制压力为0.2MPa。所得滤液过001×7聚苯乙烯磺酸型阳离子交换树脂，控制上样流速为2BV/h，用去离子水洗脱除去中性及酸性杂志，控制洗脱流速为3BV/h。再用1％Na2CO3碱化，70％乙醇洗脱，每100mL接收一次洗脱液，薄层色谱检测，收集碘化铋钾呈阳性的洗脱液。将洗脱液浓缩，用二氯甲烷溶解，过滤，重结晶即得到白毛茛碱。
上述所得固体经过HPLC，波长254nm下测定其纯度为99.0％，液相图参照附图1。
将得到的化合物通过1H-NMR、13C-NMR进行结构鉴定，结合相关文献报道确定该化合物为白毛茛碱。Blasko G,Gula D J,Shamma M.The phthalideisoquinolinealkaloids.Journal of Natural Products,1982,45(2):105-122.
核磁谱图参照附图2-3，所得白毛茛碱数据如下：无色块状晶体，溶于氯仿，分子式为C21H21NO6，分子量为383.3。
1H-NMR(400MHz，CDCl3)，δH6.51(1H,d,J＝8.2Hz,H-7’)，7.07(1H,d,J＝8.2Hz,H-6’)，6.38(1H,s,H-8)，6.58(1H,s,H-5)，3.98(1H,d,J＝3.9Hz,H-1)，5.49(1H,d,J＝3.9Hz,H-1’)，5.90(2H,d,J＝1.7Hz,-OCH2O-)，3.88(3H,s,-OCH3),4.06(3H,s,-OCH3)，2.55(3H,s,-NCH3)，2.26-2.89(4H,m)。
13C-NMR(100MHz，CDCl3)，66.1(C-1)，49.1(C-3)，26.7(C-4)，124.6(C-4α)，108.5(C-5)，146.7(C-6)，145.8(C-7)，107.8(C-8)，130.3(C-8α),82.9(C-1’α)，167.7(-CO)，118.6(C-3’α)，148.0(C-4’)，152.5(C-5’)，119.7(C-6’)，117.6(C-7’)，140.8(C-7’α)，100.8(-OCH2O-)，61.6(-OCH3)，56.6(-OCH3)，44.9(N-CH3)。
Claims (5)
1.一种从赛北紫堇中提取分离白毛茛碱的方法，其特征在于该方法的具体步骤如下：
步骤1.粉碎、碱化：将赛北紫堇全草阴干，粉碎至40-60目，得到赛北紫堇粉末，加入Na2CO3溶液浸泡3-4小时，晾干后过40-60目筛；
步骤2.超临界提取：将处理好的赛北紫堇粉末装入超临界萃取釜中，超临界CO2萃取，用乙醇溶液为夹带剂动态提取，解析萃取液并回收乙醇，得到粗生物碱；
步骤3.微滤：将粗生物碱浸膏溶解在酸水中并调节溶液pH值至2-3，将此溶液用孔径在0.5-1.0微米的陶瓷膜进行微滤处理，控制微滤温度在25-35℃，微滤压力在0.5-0.7MPa，除去颗粒物和高分子物质；
步骤4.超滤：将微滤后的溶液用聚砜中空纤维超滤膜进行超滤处理，分子截留量在4000-8000D，控制超滤压力在0.1-0.3MPa，操作温度为25-35℃，溶液pH值维持在2-3，除去大分子物质的多糖、胶质、蛋白质及色素；
步骤5.离子交换树脂分离：将所得滤液过处理好的酸性阳离子交换树脂柱，调节上样流速，先用去离子水冲洗至中性，除去水溶性小分子杂质，再调节洗脱流速用1％Na2CO3溶液碱化50-80％乙醇洗脱，收集洗脱液用碘化铋钾显色剂检测，直至无生物碱流出为止，合并检测呈阳性的洗脱液；
步骤6.重结晶：将所得的上述洗脱液减压浓缩、干燥，加入二氯甲烷溶解过滤，然后用常规方法重结晶，过滤，得到结晶物即为白毛茛碱。
2.根据权利要求1所述的一种从赛北紫堇中提取分离白毛茛碱的方法，其特征在于：所述的步骤1中，加入的Na2CO3溶液pH值为10-11，赛北紫堇粉末与Na2CO3溶液的质量比为1:1.5-1:2。
3.根据权利要求1所述的一种从赛北紫堇中提取分离白毛茛碱的方法，其特征在于：所述的步骤2中，调节萃取温度为30～45℃，萃取压力为20～30MPa，夹带剂为90％的乙醇溶液，萃取时间为2-4小时状态为动态提取，流速为1.0-1.5mL/min。
4.根据权利要求1所述的一种从赛北紫堇中提取分离白毛茛碱的方法，其特征在于：步骤3中，粗生物碱与酸水的质量比为1:20-1:40；酸水溶液为盐酸或硫酸溶液。
5.根据权利要求1所述的一种从赛北紫堇中提取分离白毛茛碱的方法，其特征在于：步骤5中，所述的酸性阳离子交换树脂采用001×7聚苯乙烯磺酸型阳离子交换树脂；上样流速为1-2BV/h，洗脱流速为2-3BV/h。
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