CN1903849A - 从欧洲红豆杉枝叶中提取分离10－去乙酰基巴卡汀ⅲ的方法 - Google Patents
从欧洲红豆杉枝叶中提取分离10－去乙酰基巴卡汀ⅲ的方法 Download PDFInfo
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Abstract
本发明公开了一种从欧洲红豆杉提取10－去乙酰基巴卡汀III(10－DAB)(10－deacetyl baccatinIII)的方法。用0.5％－3％浓度的有机弱酸水溶液浸取粉碎或未预粉碎的红豆杉枝叶。得到的浸取液用氯仿、二氯甲烷或者乙酸乙酯提取。蒸去溶剂，得到粘状物中加入乙腈，尽量使其溶解，得到的混合物放置冷却析晶，得到粗品。粗品用热甲醇溶解，过滤，除去不溶物。滤液冷却析晶，即可得到90％以上10－去乙酰基巴卡汀III产品，进一步重结晶可得纯度98％。本发明操作简单，流程短。溶剂可回收套用，成本低。
Description
技术领域
本发明涉及一种从欧洲红豆杉枝叶中提取分离10-去乙酰基巴卡汀III的方法，特别是用有机酸的水溶液对红豆杉枝叶进行渗滤浸取，有机溶剂萃取后蒸干的浸取膏用乙腈溶解将10-去乙酰基巴卡汀III析出的方法。
技术背景
10-去乙酰基巴卡汀III(10-DABIII)是人工半合成抗癌药紫杉醇(Taxol)和多西紫杉醇(docetaxel)的前体原料。紫杉醇是由紫杉的树干、树皮或针叶中提取或半合成的有效成分，多西紫杉醇是人工合成的新化合物。它们具有较广的抗癌谱，对顺铂、多柔比星等耐药肿瘤细胞株有效。紫杉醇或多西紫杉醇能与肿瘤细胞微管蛋白结合，促进微管聚合，抑制微管解聚，阻断有丝分裂，从而抑制肿瘤生长。临床已证实紫杉醇或多西紫杉醇对晚期卵巢癌、肺癌、乳腺癌、头颈部癌等有明确的抗肿瘤作用，目前其临床应用又扩大到各软组织癌，白血病及肠胃道癌等，紫杉醇被认为是迄今人类发现的疗效最好的抗癌药。随着紫杉醇和多西紫杉醇在临床上的广泛应用，，其原料的需求量也日益增加。
由于用来提取紫杉醇的天然红豆杉资源有限，且天然红豆杉植物属于国家珍稀保护植物，因而紫杉醇原料的生产和供应受到限制，远远不能满足紫杉醇临床的应用。现在人们大规模种植红豆杉树，从枝叶中提取10-DABIII，利用10-DABIII来制备合成紫杉醇和多西紫杉醇，以满足临床需求。人们研究认为，欧洲红豆杉枝叶中，10-DABIII含量较高，达到0.08％-0.15％左右。因而寻找一种简便快捷，成本低的从欧洲红豆杉中提取10-DABIII方法，有很重要的意义。
目前有关10-DABIII方法大多用脂肪醇来提取原料，U.S.Pat.No.5,393,895，U.S.Pat.No.5,453,521，U.S.Pat.No.6,002,024，WO 94/07882，CN1473821A等专利介绍了用乙醇或甲醇对紫杉植物的枝叶进行提取，得到浸取膏再通过重结晶或者色谱柱分离，得到10-DABIII及其同系物。也有一些专利文献如WO 94/07881，U.S.Pat.No.5,736,366，CN1660827等报道采用大孔吸附树脂进行富集提取10-DABIII方法。另外还出现用液态二氧化碳在超临界状态下进行紫杉醇和10-DABIII等同系物的提取分离方法。这些方法在大规模工业生产上存在各种不利因素，成本高，对条件要求苛刻，操作不易掌握等等。而本发明目的就是提供一种从红豆杉植物的枝叶中提取10-DABIII及其同系物的简单实用的方法。
本发明的目的可以通过以下技术方案来实现：用5～10倍重的0.5％-3％浓度的有机酸稀溶液浸泡粉碎或未预粉碎的欧洲红豆杉枝叶，得到的浸取液用有机溶剂提取。蒸去溶剂，得到粘状物中加入乙腈，尽量使其溶解，得到的混合物放置冷却析晶，得到粗品。粗品用热甲醇溶解，过滤，除去不溶物。滤液冷却析晶，即可得到90％以上10-去乙酰基巴卡汀III产品。重结晶可得98％的10-去乙酰基巴卡汀III。有机酸稀水溶液采用的有机酸为柠檬酸、醋酸；有机溶剂为二氯甲烷、氯仿、乙酸乙酯。
本发明要点是在低浓度有机弱酸浸提得到浸取膏后，只用乙腈析晶，甲醇重结晶即可得到较高纯度的10-去乙酰基巴卡汀III产品，省去了层析分离等步骤，操作简单，对生产条件要求低，适用于大规模生产10-DABIII及其同系物。10-去乙酰基巴卡汀III用HNMR进行结构确认，含量用HPLC测定。
具体实施方式：
试验用材料：欧洲红豆杉短枝叶，风干。
案例1
取1Kg干燥欧洲红豆杉枝叶，粉碎，放到下面带控制阀的容器中，用8L1％柠檬酸水溶液浸泡12小时，打开阀门开始渗滤。得到浸取液为黄褐色或暗绿色。用3L的氯仿分3次提取。提取液减压蒸千，得到黄褐色粘稠状浸取膏14g。向浸取膏中加入50mL乙腈，加热，混合物中有白色沉淀生成。冷却析晶，过滤得到1.5克固体.。将得到的固体用20ml左右甲醇加热溶解，趁热快速过滤。滤液冷却析晶。过滤得到1.2克10-DABIII的白色晶体。
案例2
取1Kg干燥欧洲红豆杉枝叶，不粉碎，放到下面带控制阀的容器中，用8L 0.5％乙酸水溶液浸泡12小时，打开阀门开始渗滤。得到浸取液为黄色到黄褐色。用3L的氯仿分3次提取。提取液减压蒸干，得到黄褐色粘稠状浸取膏15g。向浸取膏中加入50mL乙腈，加热，混合物中有白色沉淀生成。冷却析晶，过滤，得到1.3克滤饼，用20ml左右甲醇加热溶解，趁热快速过滤。滤液冷却析晶。过滤干燥，得到1.1克10-DABIII的白色晶体。
案例3
取100Kg干燥欧洲红豆杉枝叶，不粉碎，放到下面带控制阀的2T浸提容器中，用800L1％柠檬酸水溶液浸泡24小时，打开阀门开始渗滤。得到浸取液为黄色到黄褐色。用300L的氯仿分3次提取。提取液减压蒸干，得到深褐色粘稠状浸取膏。向浸取膏中加入5L乙腈，加热，机械搅拌，冷却析晶，过滤，得到滤饼用3L左右甲醇加热溶解，趁热快速过滤。滤液冷却析晶。过滤干燥得到约116克10-DABIII的白色晶体。
Claims (4)
1.一种从红豆杉提取10-去乙酰基巴卡汀III的方法，用0.5％-3％浓度的有机弱酸水溶液浸取，有机溶剂提取浸取液，蒸干溶剂，浸取膏用乙腈析晶，甲醇重结晶。
2.依权利要求1所述，其特征在于红豆杉枝叶是欧洲红豆杉(TaxusBaccata)。
3.依权利要求1所述，其特征是有机弱酸水为柠檬酸或乙酸水溶液，浓度范围0.5％-3％；用来提取浸取液的有机溶剂为氯仿、二氯甲烷或者乙酸乙酯。
4.依权利要求1所述，其特征在于用乙腈溶解浓缩浸取膏，同时将10-去乙酰基巴卡汀III从浓缩浸取膏液中析出，得到粗品。
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| CN101230053B (zh) * | 2007-12-04 | 2010-06-02 | 北京诺瑞医药技术有限公司 | 从红豆杉枝叶中超声提取分离10-去乙酰基巴卡汀ⅲ的方法 |
| CN103319441A (zh) * | 2013-06-17 | 2013-09-25 | 江苏红豆杉药业有限公司 | 一种从红豆杉枝叶中分离提纯10-去乙酰基巴卡亭ⅲ的方法 |
| US20150050093A1 (en) * | 2013-08-19 | 2015-02-19 | The Boeing Company | Fluid-Fed Vacuum Cutters |
| CN110003145A (zh) * | 2019-04-15 | 2019-07-12 | 云南汉德生物技术有限公司 | 一种从红豆杉中提取10-去乙酰基巴卡亭ⅲ的方法 |
| CN110845450A (zh) * | 2019-11-28 | 2020-02-28 | 云南皓瑞逸生物科技有限公司 | 一种利用粗膏或结晶过程产物生产10-dab半成品的方法 |
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| US5453521A (en) * | 1992-10-05 | 1995-09-26 | Rhone-Poulenc Rorer S.A. | Process for obtaining 10-deacetylbaccatin III |
| FR2696462B1 (fr) * | 1992-10-05 | 1994-11-25 | Rhone Poulenc Rorer Sa | Procédé d'obtention de la désacétyl-10 baccatine III. |
| US6002024A (en) * | 1998-07-27 | 1999-12-14 | Dabur Research Foundation | Process for the isolation of 14β-hydroxy-10-deacetyl baccatin-III |
| US6495705B2 (en) * | 2000-03-16 | 2002-12-17 | Napro Biotherapeutics, Inc. | Efficient process for the production of 10-DAB III by selective hydrazinolysis of various taxanes |
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| CN1298712C (zh) * | 2004-12-27 | 2007-02-07 | 梅县梅雁生物工程研究所 | 从红豆杉枝叶中初分离10－去乙酰基巴卡亭ⅲ的方法 |
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2006
- 2006-08-15 CN CNB2006100892875A patent/CN100404520C/zh not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101230053B (zh) * | 2007-12-04 | 2010-06-02 | 北京诺瑞医药技术有限公司 | 从红豆杉枝叶中超声提取分离10-去乙酰基巴卡汀ⅲ的方法 |
| CN103319441A (zh) * | 2013-06-17 | 2013-09-25 | 江苏红豆杉药业有限公司 | 一种从红豆杉枝叶中分离提纯10-去乙酰基巴卡亭ⅲ的方法 |
| US20150050093A1 (en) * | 2013-08-19 | 2015-02-19 | The Boeing Company | Fluid-Fed Vacuum Cutters |
| US9555480B2 (en) * | 2013-08-19 | 2017-01-31 | The Boeing Company | Fluid-fed vacuum cutters |
| CN110003145A (zh) * | 2019-04-15 | 2019-07-12 | 云南汉德生物技术有限公司 | 一种从红豆杉中提取10-去乙酰基巴卡亭ⅲ的方法 |
| CN110845450A (zh) * | 2019-11-28 | 2020-02-28 | 云南皓瑞逸生物科技有限公司 | 一种利用粗膏或结晶过程产物生产10-dab半成品的方法 |
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| CN100404520C (zh) | 2008-07-23 |
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