CN101444720A - 高选择性氢键吸附树脂及用于银杏叶提取物中有效成分的分离纯化 - Google Patents
高选择性氢键吸附树脂及用于银杏叶提取物中有效成分的分离纯化 Download PDFInfo
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Abstract
一种高选择性氢键吸附树脂,解决银杏叶提取物中有效成分黄酮和内酯的有效分离纯化问题。本发明以交联度为6%的DVB-co-MA树脂为母体球,以N,N-二甲基甲酰胺充分溶胀后,加入二胺进行胺解反应,得到黄色树脂;黄色树脂干燥后,以酰化反应试剂-二酸酐充分浸泡,经酰化反应得到带有酰胺间隔臂的吸附树脂,即本发明的树脂,该树脂的结构式如下式。该树脂在分离银杏叶粗提物中黄酮和内酯的步骤是:将市售银杏叶提取物溶解在乙醇水溶液中制得上柱液;室温下,将上柱液通过装有本发明树脂的吸附柱,其中黄酮被树脂吸附而保留在树脂柱上,内酯不能被树脂吸附而从树脂柱中流出;分别收集流出液和洗脱液,真空干燥后即得纯化后的黄酮和内酯。
Description
【技术领域】
本发明属于吸附分离树脂的结构设计及天然植物有效成分分离纯化技术领域,特别涉及一种带有酰胺间隔臂的高选择性氢键吸附树脂的合成方法及利用所合成的吸附树脂,建立银杏叶提取物中两种有效成分—黄酮和内酯的树脂法分离工艺。
【背景技术】
随着生活条件、生存环境的变化,人类健康水平也大幅度的提高,现代疾病正在或已经取代了以往的传染性疾病,人类的医疗模式由单纯的疾病治疗转变为预防、保健、治疗、康复相结合,各种替代医学和传统医学发挥着越来越大的作用,世界范围内掀起了“回归自然”的热潮,来自绿色生命植物的天然药物因其较高的安全性、独特的药理和生理活性逐渐引起人们的重视。
在天然植物药的开发中,银杏叶的现代药用研究无疑是其中的热点问题之一。七十年代初,德国首先用溶剂萃取的方法大规模生产具有明确质量标准的银杏叶提取物EGb761,为黄酮甙(含量在24%以上)和萜内酯(银杏内酯和白果内酯的总和,含量在6%以上)的混合物,并以此开发成了疗效显著、稳定的治疗心脑血管疾病的单方植物药,成为欧洲最为畅销的药品,引起了国际医药界极大的关注。【K.Chandrasekaran,Z.Mehrabian,B.Spinnewyn,K.Drieu,G.Fiskum,Brain Res.922(2001):282.】。但是,随着研究的深入,大量的药理和临床实验都证明了银杏叶提取物中的主要药效成分黄酮和内酯的药理作用并不完全相同,【E.M.Middleton,A.H.Teramura,Plant Physiology,103(1993)741.】,它们二者不同的配比可能达到不同的药效,特别是自从1984年P.Braquet领导的法国研究小组首次证明了银杏内酯对血小板活化因子(PAF)受体强大的特异性抑制作用以来,银杏内酯作为目前最强有力的天然PAF受体阻断剂,在治疗哮喘、内毒素休克、器官移植排斥反应、心脑血管疾病及多种炎症疾病等方面进行了很多的临床应用研究,取得了令人瞩目的成果。【P.Braquet,Drug.Future,12(1987)643.】。以上这些关于银杏叶深入的药理和药效研究以及银杏制剂的药用开发都迫切需要大量的单一组分提取物的试验样品,这就对银杏叶中两种有效成分的分离纯化提出了很高的要求。目前的分离工艺仍以日本专利的分离方法为主,【J.Oreilly,WO 9633728,1996】,涉及到溶剂萃取、活性炭脱色、重结晶等多个步骤,工艺繁琐、有效成分损失较大,特别是在分离中使用大量的低沸点、强毒性的有机溶剂,环境污染较大。近年来,树脂吸附法在天然产物的提取分离方面显示了独特的优越性,与常用的溶剂萃取法相比,工艺设备简单,投资较少,提取收率较高,生产成本可大大降低,同时,该方法使用溶剂较少,常常只用水和酒精,且大部分酒精可以回收,属于环境友好工艺,在技术水平上有很强的竞争力。但是,目前使用的吸附树脂选择性较差,不能满足性质相近的组分分离,因此在银杏叶有效成分的分离中难以得到令人满意的结果,常在树脂分离工艺后仍需辅助溶剂萃取、活性炭脱色等步骤,树脂法的优势并未体现出来。【韩金玉,颜迎春等,银杏萜内酯提取与纯化技术,中草药,2002年第33卷第11期】。
【发明内容】
本发明的目的是克服现有技术的不足,提供一种带有酰胺间隔臂的、具有氢键作用能力的高选择性氢键吸附树脂及用于银杏叶提取物中有效成分的分离纯化。
本发明针对银杏叶提取物中两种有效成分—黄酮和内酯的分子结构特点,设计合成了带有特殊功能基的新型高选择性吸附树脂,可大大提高树脂对黄酮的吸附能力,只需“吸附—解吸”一步,即可将黄酮和内酯分离,因此,该工艺操作简便、高效、环境友好、适于大规模工业化生产,只经“吸附—解吸”一步连续工艺,即可实现黄酮和内酯的完全分离,同时得到两个产品,即不含内酯的黄酮提取物和不含黄酮的内酯提取物,这将为深入的药理、药效研究提供大量的试验样品,对于银杏叶的药用研究和开发具有重要的意义。
本发明为实现上述目的公开了一种带有酰胺间隔臂的高选择性氢键吸附树脂,该树脂的结构式如下:
其中,n=2~6,m=0~4,母体球为交联度6%的DVB-co-MA树脂,其形状为球形,粒径0.3~1.0mm,平均孔径为10~30nm,孔隙率50~65%。
本发明提供的吸附树脂的合成方法,主要通过以下步骤实现:
第一、以交联度为6%的DVB-co-MA树脂为母体球(树脂为球形,粒径0.3~1.0mm,平均孔径为10~30nm,孔隙率50~65%),将其充分干燥,装入三口瓶中,以N,N—二甲基甲酰胺充分溶胀后,加入占母体球质量50~200%的二胺为胺解反应试剂,在60~140℃反应8~12小时后,停止反应,静置至室温,经过滤、洗涤处理后得到黄色树脂。反应过程如下式所示:
第二、将上步得到的黄色树脂干燥后,在三口瓶中以酰化反应试剂—二酸酐充分浸泡,二酸酐用量为黄色树脂质量的2~5倍,升温至70~100℃反应7~10小时,停止反应,静置至室温,经过滤、洗涤后,得到带有酰胺间隔臂的吸附树脂,即本发明的树脂,树脂编号为Pnm(其中n=2~6,m=0~4)。反应过程如下式所示:
本发明还公开了氢键吸附树脂在分离银杏叶粗提物中黄酮和内酯的应用,该应用包括以下步骤:
第一、将黄酮质量百分含量为24~26%、内酯质量百分含量为6—6.5%的市售银杏叶提取物溶解在体积浓度为6%~10%的乙醇水溶液中,制得上柱液,上柱液浓度为5—8mg提取物/ml;
第二、将本发明所合成的吸附树脂装入吸附柱中,吸附柱直径与柱长的比为1:5—1:20;
第三、室温下,将上柱液以0.5~1.0BV/小时的流速通过树脂吸附柱,树脂的处理量为1ml上柱液/ml湿树脂。吸附完成后,黄酮被树脂吸附而保留在树脂柱上,同时,内酯由于无法与树脂产生有效的吸附结合力,不能被树脂吸附,从树脂柱中流出;
第四、收集流出液,蒸干后经真空干燥得到白色固体,经HPLC检测,其中内酯质量百分含量为30~50%,黄酮没有检出;
第五、以体积浓度为60~80%的乙醇溶液洗脱树脂,解吸速度为0.5~1.0BV/h,洗脱液经减压蒸馏回收乙醇,真空干燥后,得到淡黄色固体,经HPLC检测,其中黄酮质量百分含量为30%~50%,内酯没有检出。
本发明的有益效果是:
本发明针对银杏叶提取物中两种重要的有效成分—黄酮和内酯的分子结构特点,设计合成了一类带有酰胺间隔臂的高选择性氢键吸附树脂,利用特异性的氢键作用,大大提高了树脂对黄酮的吸附能力,只经“吸附—解吸”一步连续工艺,即可实现黄酮和内酯的完全分离,同时得到两个产品,即不含内酯的黄酮提取物和不含黄酮的内酯提取物。本发明所合成的树脂,对黄酮类物质吸附选择性高,所建立的黄酮和内酯树脂法分离工艺操作简单、分离效率高、环境友好、生产成本低,避免大量使用强毒性、易挥发、易燃的有机溶剂,对于银杏叶提取物的进一步药用研究具有重要的实际应用价值。
【具体实施方式】
实施例1
在500ml三口瓶中加入母体球(即交联度为6%的DVB-co-MA树脂)100g,以400mlN,N—二甲基甲酰胺充分溶胀,加入50g 1,2—乙二胺(即胺解反应试剂中n=2),搅拌均匀后,升温至80℃反应10小时,反应完成后,经过洗涤处理后得到黄色树脂。
在500ml三口瓶中加入上述黄色树脂100g,加入200ml丁二酸酐(即酰化反应试剂中m=2),充分混合后,在100℃反应9小时,反应完成后,经过洗涤处理后得到浅黄色树脂,为本发明树脂,编号为P22。
实施例2
在500ml三口瓶中加入母体球(即交联度为6%的DVB-co-MA树脂)100g,以400mlN,N—二甲基甲酰胺充分溶胀,加入150g 1,6—己二胺(即胺解反应试剂中n=6),搅拌均匀后,升温至130℃反应12小时,反应完成后,经过洗涤处理后得到黄色树脂。
在500ml三口瓶中加入上述黄色树脂100g,加入300ml丙二酸酐(即酰化反应试剂中m=1),充分混合后,在80℃反应8小时,反应完成后,经过洗涤处理后得到浅黄色树脂,为本发明树脂,编号为P61。
实施例3
在5升三口瓶中加入母体球(即交联度为6%的DVB-co-MA树脂)1kg,以4升N,N—二甲基甲酰胺充分溶胀,加入1kg 1,2—乙二胺(即胺解反应试剂中n=2),搅拌均匀后,升温至100℃反应12小时,反应完成后,经过洗涤处理后得到黄色树脂。
在5升三口瓶中加入上述黄色树脂2kg,加入4kg乙二酸酐(即酰化反应试剂中m=0),充分混合后,在80℃反应10小时,反应完成后,经过洗涤处理后得到浅黄色树脂,为本发明树脂,编号为P20。
实施例4
在5升三口瓶中加入母体球(即交联度为6%的DVB-co-MA树脂)1kg,以4升N,N—二甲基甲酰胺充分溶胀,加入1.5kg1,4—丁二胺(即胺解反应试剂中n=4),搅拌均匀后,升温至110℃反应10小时,反应完成后,经过洗涤处理后得到黄色树脂。
在5升三口瓶中加入上述黄色树脂1.5kg,加入6kg己二酸酐(即酰化反应试剂中m=4),充分混合后,在100℃反应10小时,反应完成后,经过洗涤处理后得到浅黄色树脂,为本发明树脂,编号为P44。
实施例5
在500ml三口瓶中加入母体球(即交联度为6%的DVB-co-MA树脂)100g,以400mlN,N—二甲基甲酰胺充分溶胀,加入200g 1,5—戊二胺(即胺解反应试剂中n=2),搅拌均匀后,升温至80℃反应10小时,反应完成后,经过洗涤处理后得到黄色树脂。
在500ml三口瓶中加入上述黄色树脂100g,加入500ml丁二酸酐(即酰化反应试剂中m=2),充分混合后,在100℃反应9小时,反应完成后,经过洗涤处理后得到浅黄色树脂,为本发明树脂,编号为P52。
实施例6
将含有黄酮24%(w%)、内酯含量6%(w%)的银杏提取物240mg溶解于40ml 7%(v/v)乙醇水溶液,制成上柱液(上柱液浓度为6.0mg提取物/ml),通过装有本发明树脂P44的树脂柱(柱长30cm,内径18mm,装有40ml湿树脂),吸附速度为1.0BV/h,吸附完成后,收集流出液,用去离子水清洗树脂柱,接着用80%(v/v)乙醇水溶液解吸,洗脱流速为0.5BV/h,收集解吸液。分别将流出液和解吸液蒸干,真空干燥后得到两个产品,一是流出液蒸干后的白色粉末,经HPLC检测,内酯含量30.2%(w%),黄酮未检出;另外一个是解吸液蒸干后的淡黄色粉末,经HPLC检测,黄酮含量为36.3%(w%),内酯未检出。
实施例7
将含有黄酮25.2%(w%)、内酯含量6.3%(w%)的银杏提取物2800mg溶解于400ml10%(v/v)乙醇水溶液,制成上柱液(上柱液浓度为7.0mg提取物/ml),通过装有本发明树脂P20的树脂柱(柱长50cm,内径50mm,装有400ml湿树脂),吸附速度为0.5BV/h,吸附完成后,收集流出液,用去离子水清洗树脂柱,接着用70%(v/v)乙醇水溶液解吸,洗脱流速为1.0BV/h,收集解吸液。分别将流出液和解吸液蒸干,真空干燥后得到两个产品,一是流出液蒸干后的白色粉末,经HPLC检测,内酯含量48.3%(w%),黄酮未检出;另外一个是解吸液蒸干后的淡黄色粉末,经HPLC检测,黄酮含量为47.3%(w%),内酯未检出。
实施例8
将含有黄酮含量24%(w%)、内酯含量6%(w%)的银杏提取物600mg溶解于120ml8%(v/v)乙醇水溶液中,制成上柱液(上柱液浓度为5.0mg提取物/ml),通过装有本发明树脂P61的树脂柱(柱长40cm,内径40mm,装有120ml湿树脂),吸附速度为0.8BV/h,吸附完成后,收集流出液,用去离子水清洗树脂柱,接着用80%(v/v)乙醇水溶液解吸,洗脱流速为0.8BV/h,收集解吸液。分别将流出液和解吸液蒸干,真空干燥后得到两个产品,一是流出液蒸干后的白色粉末,经HPLC检测,内酯含量30.1%(w%),黄酮未检出;另外一个是解吸液蒸干后的淡黄色粉末,经HPLC检测,黄酮含量为41.3%(w%),内酯未检出。
实施例9
将含有黄酮24.7%(w%)、内酯含量6.1%(w%)的银杏提取物3200mg溶解于400ml10%(v/v)乙醇水溶液,制成上柱液(上柱液浓度为8.0mg提取物/ml),通过装有本发明树脂P22的树脂柱(柱长50cm,内径50mm,装有400ml湿树脂),吸附速度为0.5BV/h,吸附完成后,收集流出液,用去离子水清洗树脂柱,接着用70%(v/v)乙醇水溶液解吸,洗脱流速为1.0BV/h,收集解吸液。分别将流出液和解吸液蒸干,真空干燥后得到两个产品,一是流出液蒸干后的白色粉末,经HPLC检测,内酯含量31.3%(w%)黄酮未检出;另外一个是解吸液蒸干后的淡黄色粉末,经HPLC检测,黄酮含量为32.3%(w%),内酯未检出。
实施例10
将含有黄酮24.1%(w%)、内酯含量6.1%(w%)的银杏提取物220mg溶解于40ml10%(v/v)乙醇水溶液,制成上柱液(上柱液浓度为5.5mg提取物/ml),通过装有本发明树脂P52的树脂柱(柱长30cm,内径18mm,装有40ml湿树脂),吸附速度为0.8BV/h,吸附完成后,收集流出液,用去离子水清洗树脂柱,接着用70%(v/v)乙醇水溶液解吸,洗脱流速为1.0BV/h,收集解吸液。分别将流出液和解吸液蒸干,真空干燥后得到两个产品,一是流出液蒸干后的白色粉末,经HPLC检测,内酯含量32.5%(w%),黄酮未检出;另外一个是解吸液蒸干后的淡黄色粉末,经HPLC检测,黄酮含量为31.8%(w%),内酯未检出。
Claims (5)
1、一种带有酰胺间隔臂的高选择性氢键吸附树脂,该树脂的结构式如下:
其中,n=2~6,m=0~4,母体球为交联度6%的DVB-co-MA树脂。
2、根据权利要求1所述的树脂,其特征在于DVB-co-MA树脂为球形,粒径0.3~1.0mm,平均孔径为10~30nm,孔隙率50~65%。
3、一种权利要求1所述的树脂的合成方法,其特征在于该方法通过以下步骤实现:
第一、以交联度为6%的DVB-co-MA树脂为母体球,将其充分干燥,装入三口瓶中,以N,N—二甲基甲酰胺充分溶胀后,加入占母体球质量50~200%的二胺为胺解反应试剂,在60~140℃反应8~12小时后,停止反应,静置至室温,经过滤、洗涤处理后得到黄色树脂,反应过程如下式所示:
第二、将上步得到的黄色树脂干燥后,在三口瓶中以酰化反应试剂—二酸酐充分浸泡,二酸酐用量为黄色树脂质量的2~5倍,升温至70~100℃反应7~10小时,停止反应,静置至室温,经过滤、洗涤后,得到带有酰胺间隔臂的吸附树脂,即本发明的树脂,
反应过程如下式所示:
树脂编号为Pnm,其中n=2~6,m=0~4。
4、根据权利要求3所述的树脂的合成方法,其特征在于DVB-co-MA树脂为球形,粒径0.3~1.0mm,平均孔径为10~30nm,孔隙率50~65%。
5、一种权利要求1所述的带有酰胺间隔臂的高选择性氢键吸附树脂在分离银杏叶粗提物中黄酮和内酯的应用,该应用包括以下步骤:
第一、将黄酮质量百分含量为24~26%、内酯质量百分含量为6—6.5%的市售银杏叶提取物溶解在体积浓度为6%~10%的乙醇水溶液中,制得上柱液,上柱液浓度为5—8mg提取物/ml;
第二、将权利要求1所述的吸附树脂装入吸附柱中,吸附柱直径与柱长的比为1:5—1:20;
第三、室温下,将上柱液以0.5~1.0BV/小时的流速通过树脂吸附柱,树脂的处理量为1ml上柱液/ml湿树脂;吸附完成后,黄酮被树脂吸附而保留在树脂柱上,同时,内酯由于无法与树脂产生有效的吸附结合力,不能被树脂吸附,从树脂柱中流出;
第四、收集流出液,蒸干后经真空干燥得到白色固体,经HPLC检测,内酯质量百分含量为30~50%,黄酮没有检出;
第五、以体积浓度为60~80%的乙醇溶液洗脱树脂,解吸速度为0.5~1.0BV/h,洗脱液经减压蒸馏回收乙醇,真空干燥后,得到淡黄色固体,经HPLC检测,其中黄酮质量百分含量为30%~50%,内酯没有检出。
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CN105906587A (zh) * | 2016-04-25 | 2016-08-31 | 张玲 | 一种2,5-呋喃二甲醇纯化的方法 |
CN105944693A (zh) * | 2016-05-17 | 2016-09-21 | 张国华 | 一种含酰胺吸附材料及其合成方法 |
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US5460725A (en) * | 1994-06-21 | 1995-10-24 | The Dow Chemical Company | Polymeric adsorbents with enhanced adsorption capacity and kinetics and a process for their manufacture |
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CN105906587A (zh) * | 2016-04-25 | 2016-08-31 | 张玲 | 一种2,5-呋喃二甲醇纯化的方法 |
CN105944693A (zh) * | 2016-05-17 | 2016-09-21 | 张国华 | 一种含酰胺吸附材料及其合成方法 |
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