CN104761520B - 一种采用盐析制备高纯度丹酚酸b的方法 - Google Patents
一种采用盐析制备高纯度丹酚酸b的方法 Download PDFInfo
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- SNKFFCBZYFGCQN-UHFFFAOYSA-N 2-[3-[3-[1-carboxy-2-(3,4-dihydroxyphenyl)ethoxy]carbonyl-2-(3,4-dihydroxyphenyl)-7-hydroxy-2,3-dihydro-1-benzofuran-4-yl]prop-2-enoyloxy]-3-(3,4-dihydroxyphenyl)propanoic acid Chemical compound C=1C=C(O)C=2OC(C=3C=C(O)C(O)=CC=3)C(C(=O)OC(CC=3C=C(O)C(O)=CC=3)C(O)=O)C=2C=1C=CC(=O)OC(C(=O)O)CC1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-UHFFFAOYSA-N 0.000 title claims abstract description 89
- SNKFFCBZYFGCQN-VWUOOIFGSA-N Lithospermic acid B Natural products C([C@H](C(=O)O)OC(=O)\C=C\C=1C=2[C@H](C(=O)O[C@H](CC=3C=C(O)C(O)=CC=3)C(O)=O)[C@H](OC=2C(O)=CC=1)C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 SNKFFCBZYFGCQN-VWUOOIFGSA-N 0.000 title claims abstract description 74
- STCJJTBMWHMRCD-UHFFFAOYSA-N salvianolic acid B Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=O)C=Cc2cc(O)c(O)c3OC(C(C(=O)OC(Cc4ccc(O)c(O)c4)C(=O)O)c23)c5ccc(O)c(O)c5 STCJJTBMWHMRCD-UHFFFAOYSA-N 0.000 title claims abstract description 74
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
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- 239000002253 acid Substances 0.000 claims description 26
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
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- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
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- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 claims description 4
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
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- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 claims description 4
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
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- 229910052786 argon Inorganic materials 0.000 claims description 2
- 239000001569 carbon dioxide Substances 0.000 claims description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
一种采用盐析制备高纯度丹酚酸B的方法,其属于中药提纯技术领域。该方法采用将丹参研磨后用醇水溶液提取,过滤浓缩后溶于有机溶剂,并向其中滴加成盐剂,将丹酚酸B成盐析出,杂质仍留在溶液中;将丹酚酸B盐析出过滤后,再经过脱盐处理,得到高纯度的丹酚酸B。该方法条件温和,解决了丹酚酸B性质不稳定、易转化降解,以及原料共存多种多酚化合物和大量胶体状杂质分离纯化难度高的问题,其工艺简单方便、成本低、回收率高、纯度高。采用该方法制备的丹酚酸B含量≥98.0%,收率≥80%。
Description
技术领域:
本发明涉及一种采用盐析制备高纯度丹酚酸B的方法,其属于中药提纯技术领域。
背景技术:
丹参制剂是我国治疗心脑血管病的基本中药,因疗效确切,丹参已成为我国用量最大(1.5万吨/年)、销售额最高、生产厂最多的中药,剂型主要有滴丸、注射液、片、颗粒、冲剂和胶囊等,此外丹参还与其它药材组方,用于肺心病、高脂血症、高血粘度综合征、哮喘、支气管肺炎、肝炎、肝硬化、肾病综合征、关节炎、糖尿病循环障碍、各种细菌性和病毒性感染、抗内毒素、肿瘤、硬皮病、皮肤炎、银屑病、过敏性紫癜、红斑狼疮、血栓闭塞性脉管炎、痤疮、难治性癫痫、视网膜病变等多种疾病的预防和治疗[Int J Cardiol. 2007,121(1)9;. 医学综述,2006,12(23)1467;中国新医药,2003,2(6)54;医药导报,2004,23(7)435]。
研究表明,水溶性酚酸类化合物是其主要活性成分,具有抗氧化、抗炎、抗凝等多种有益的生物活性[Int J Cardiol. 2007,121(1)9;中国公共卫生,2007,23(4)448;时珍 国医国药,2003,14(6)371;Chin J Pharmacol Toxicol, 2003,17(5)333;时珍国医国药, 2006,17(12)2406;中药材,2002,25(9)683]。目前,以丹参总酚酸为有效成分的丹参注射液占有我国最大的中药注射剂市场,以其主要成分丹酚酸B开发的新药丹参多酚酸盐注射剂已被SFDA批准上市。但是,因原料药纯度不足所导致的药物热、过敏性休克和皮肤反应发生率分别高达16.26%、16.43%和37.4%[药物不良反应杂志,2001,3(3)156],因此,高纯度丹酚酸B的大批量制备有着极其重要价值。
目前,文献公开的丹酚酸B的制备方法有沉淀(水沉、醇沉、酸沉)、萃取、大孔树脂层析、正相色谱和反相色谱,以及这些方法联用法。如:专利CN101270103A公开了醇沉与大孔树脂吸附联用的方法;专利CN103923043A公开了酸沉与树脂联用的方法;专利CN104130226A公开了有机溶剂萃取与大孔树脂分离联用的方法;专利CN1528756A公开了醇沉+萃取+硅胶柱层析的联用方法;专利CN1981809A公开了硅胶柱层析与反相色谱的联用方法;专利CN101434590A公开了聚酰胺柱层析+大孔吸附树脂柱层析+溶剂萃取+反相色谱的联用方法;专利CN104072456A公开了大孔吸附树脂层析+反相树脂色谱的联用方法。
由于丹参中与丹酚酸B共存的不仅有丹酚酸A、B、C、D、E等多种多酚化合物,还有大量胶体状杂质。丹酚酸B性质不稳定,在酸、碱、热的作用下不仅可转变成其它多酚类化合物,还可自身氧化降解。胶体状杂质能显著改变化合物的色谱行为,对化合物的分离纯化有极大的危害。因而,目前已报道的丹酚酸B的制备工艺,或存在纯度低、杂质含量高,或存在工艺冗长、收率低、成本高的问题。市场迫切需求工艺流程简单、低成本的高纯度丹酚酸B的制备方法。
发明的技术内容:
为了解决丹酚酸B性质不稳定、易转化降解,以及原料共存多种多酚化合物和大量胶体状杂质,分离纯化难度高的问题,本发明提供了一种可简单、方便、低成本、大批量制备高纯度丹酚酸B的方法
本发明的技术方案为:一种采用盐析制备高纯度丹酚酸B的方法,包括以下步骤:
(1)将丹参粉碎后用醇溶剂、水或醇水混合液提取,过滤并减压浓缩后获得膏状丹参粗提物;
(2)将膏状丹参粗提物经过简单的纯化处理得到膏状丹酚酸B粗提物;所述纯化处理采用沉淀、萃取、大孔树脂层析、正向色谱或反向色谱;沉淀法包括酸沉、水沉和醇沉,水沉是将水不溶的低极性杂质沉淀析出,醇沉是将醇不溶的杂质沉淀析出,酸沉是将酸性条件下不溶的杂质沉淀析出。大孔树脂包括弱极性和非极性树脂如D101、AB-8、HPD-100等。反相色谱填料包括反相硅胶和反相树脂如C18硅胶、CG161、葡聚糖凝胶LH-20等。
(3)将膏状丹参粗提物或膏状丹酚酸B粗提物溶于有机溶剂,得到丹酚酸B粗溶液,在缓慢搅拌下滴加成盐剂,成盐pH为3-4,成盐温度为25-45℃,析出沉淀丹酚酸B盐;所述丹酚酸B粗溶液中的含固量为10~30%(重量百分比),所述丹酚酸B粗溶液中丹酚酸B的重量百分比含量为5~80%,成盐剂的摩尔量为丹酚酸B摩尔量的1-2.5倍,成盐剂为弱碱溶液及钾、钠、钙、镁、氨、胺的有机盐溶液或钾、钠、钙、镁、氨、胺的碳酸盐溶液;所述有机溶剂选自甲醇、乙醇、丙醇、丙酮、乙腈、四氢呋喃、二氧六环、二甲亚砜、甲酰胺或乙酸乙酯中一种或两种,以乙酸乙酯和无水乙醇的混合溶液为佳;
(4)将丹酚酸B盐经酸析脱盐法、萃取脱盐法或大孔树脂层析脱盐法脱盐,干燥后获得高纯度的丹酚酸B。
所述膏状丹参粗提物中丹酚酸B的重量百分含量为5-80%,所述膏状丹酚酸B粗提物中丹酚酸B的重量百分含量为5-80%。
所述成盐剂选自乙酸钠、丁酸钠、异辛酸钠、异辛酸钾、异辛酸钙、异辛酸四乙铵、碳酸钠、碳酸氢钠、碳酸铵、碳酸氢铵、醋酸铵、醋酸四乙铵、氨气、肼、联氨、三乙胺、二乙胺、乙二胺中的一种或两种,其中以异辛酸钠和异辛酸钾为佳;所述成盐剂的浓度为0.1~10mol/L。
所述酸析脱盐法为:将丹酚酸B盐溶于有机溶液,在搅拌下滴加浓度范围为0.1~10mol/L的醋酸、盐酸、磷酸或硫酸,使丹酚酸B盐转化为丹酚酸B留在有机溶液中,而醋酸、盐酸、磷酸或硫酸则成盐析出,过滤再将有机溶液浓缩;所述萃取脱盐法为:将酸化丹酚酸B盐溶于水,酸化使丹酚酸B盐转化为丹酚酸B后,将丹酚酸B由水相萃入乙酸乙酯相,再将乙酸乙酯相浓缩;所述大孔树脂层析脱盐法为:将丹酚酸B盐溶于水,酸化后丹酚酸B盐转化为丹酚酸B,上大孔树脂层析柱,水洗至中性后,再用乙醇将丹酚酸B洗脱,浓缩。
丹酚酸B成盐的步骤(3)中向丹酚酸B粗溶液中加入抗坏血酸或亚硫酸氢钠,再滴加成盐剂,抗坏血酸或亚硫酸氢钠的用量为2~10g/l。
丹酚酸B成盐的步骤(3)中向丹酚酸B粗溶液,在缓慢搅拌的条件下滴加成盐剂的过程在惰性气体保护下进行,所述惰性气体选自氮气、二氧化碳、氦气、氩气或氖气。
本发明的有益效果为:该方法采用将丹参研磨后用醇水溶液提取,过滤浓缩后溶于有机溶剂,并向其中滴加成盐剂,将丹酚酸B成盐析出,杂质仍留在溶液中;将丹酚酸B盐析出过滤后,再经过脱盐处理,得到高纯度的丹酚酸B。该方法条件温和,解决了丹酚酸B性质不稳定、易转化降解,以及原料共存多种多酚化合物和大量胶体状杂质分离纯化难度高的问题,其工艺简单方便、成本低、回收率高、纯度高。采用该方法制备的丹酚酸B含量≥98.0%,收率≥80%。
附图说明:
图1是丹参提取物的HPLC分析色谱图。
图2是盐析滤液的HPLC分析色谱图。
图3是盐析沉淀的HPLC分析色谱图。
图4是含量98%的丹酚酸B的HPLC分析色谱图。
具体实施方式:
实施例1:
将 1000 g丹参粉碎后用 8000ml 无水乙醇 3 次提取,过滤并减压浓缩后获膏状物 450 g(含丹酚酸B 29.25 g,含量 6.50 %);去离子水分散浸膏后与乙酸乙酯进行萃取,乙酸乙酯萃取相浓缩后获膏状物 79.93 g(含丹酚酸B 27.96 g,含量 34.98 %);用2400ml的乙酸乙酯和无水乙醇(1:1)的混合溶液溶解膏状物,缓慢搅拌并滴加 156 ml 0.5mol/L的异辛酸钾-乙醇溶液,在37℃、溶液pH 为4的条件下静置24小时后过滤得到沉淀 30.95 g(含丹酚酸B 26.57 g,含量85.85%,)。将所得丹酚酸B钾盐在 200 ml无水乙醇中溶解后,滴加冰醋酸调pH为3,搅拌24h,滤除s生成的固体后将滤液减压浓缩获固体 26.88 g(含丹酚酸B 25.86 g,含量 96.21 %);用150 ml去离子水溶解固体,加入等体积乙酸乙酯萃取,共萃取三次,合并乙酸乙酯相萃取液,减压浓缩获得含量为98.10%的丹酚酸B 22.96 g,收率80.0%。
实施例2:
将 1000 g丹参粉碎后用 8000ml 70%乙醇水 3 次提取,过滤并减压浓缩后获膏状物 456 g(含丹酚酸B 30.05 g,含量 6.59 %);用4600 ml的乙酸乙酯和甲醇(1:1)的混合溶液溶解膏状物,缓慢搅拌并滴加 210 ml 0.5mol/L的异辛酸钠-乙醇溶液,在40℃、溶液pH 为3的条件下静置24小时后过滤得到沉淀 31.09 g(含丹酚酸B 26.83 g,含量86.29%)。将所得丹酚酸B钠盐在 200 ml甲醇中溶解后,滴加盐酸调pH为3,搅拌24h,滤除生成的固体后将滤液减压浓缩获固体 26.62 g(含丹酚酸B 25.52 g,含量 95.86 %);用150ml去离子水溶解固体,采用HPD-100大孔吸附树脂柱进行洗脱,分别用水及乙醇冲洗,收集乙醇洗脱部分,减压浓缩获得含量为98.03%的丹酚酸B 24.10 g,收率81.8%。
实施例3:
将 1000 g丹参粉碎后用 8000ml 去离子水 3 次提取,过滤并减压浓缩后获膏状物 472 g(含丹酚酸B 29.92 g,含量 6.34 %);用乙酸乙酯溶解膏状物,滤除不溶固体,向溶液中加入400g硅胶(200-300目)干法拌样后进行硅胶柱层析富集,石油醚-乙酸乙酯梯度洗脱,收集含丹酚酸B部分,合并浓缩后获膏状物 48.68 g(含丹酚酸B 28.39 g,含量58.32 %);用730 ml的丙醇溶解膏状物,缓慢搅拌并滴加 80 ml 0.5mol/L的醋酸铵-乙醇溶液,在35℃、溶液pH 为4的条件下静置24小时后过滤所得沉淀 30.79 g(含丹酚酸B25.56 g,含量83.02%)。将所得丹酚酸B铵盐在 200 ml无水乙醇中溶解后,滴加硫酸调pH为3,搅拌24h,滤除生成的固体后将滤液减压浓缩获固体 26.10 g(含丹酚酸B 24.79 g,含量94.98 %);用150 ml去离子水溶解固体,采用AB-8大孔吸附树脂柱进行洗脱,分别用水及乙醇冲洗,收集乙醇洗脱部分,减压浓缩获得含量为98.08%的丹酚酸B 23.48g,收率80.0%。
实施例4:
将 1000 g丹参粉碎后用 8000ml 50%甲醇水 3 次提取,过滤并减压浓缩后获膏状物 461 g(含丹酚酸B 30.52 g,含量 6.62 %);采用10%乙醇水溶解浸膏,采用D101大孔吸附树脂柱进行洗脱,分别用水及乙醇冲洗,收集乙醇洗脱部分后浓缩至无醇味,进行CG161树脂进行精细分离,采用乙醇-水梯度洗脱,收集含丹酚酸B部分溶液,合并浓缩后获膏状物 34.26 g(含丹酚酸B 27.48 g,含量 80.2 %);用860 ml的乙酸乙酯溶液溶解膏状物,缓慢搅拌并滴加 114 ml 0.5mol/L的三乙胺-乙醇溶液,在45℃、溶液pH 为3的条件下静置24小时后过滤所得沉淀 29.51 g(含丹酚酸B 25.98 g,含量88.03%)。将所得丹酚酸B盐在 200 ml甲醇中溶解后,滴加磷酸调pH为3,搅拌24h,滤除生成的固体后将滤液减压浓缩获固体 26.24 g(含丹酚酸B 25.01 g,含量 95.32 %);用150 ml去离子水溶解固体,加入等体积乙酸乙酯萃取,共萃取三次,合并乙酸乙酯相萃取液,减压浓缩获得含量为98.04%的丹酚酸B 24.12 g,收率80.6%。
Claims (4)
1.一种采用盐析制备高纯度丹酚酸B的方法,其特征在于,包括以下步骤:
(1)将丹参粉碎后用醇溶剂、水或醇水混合液提取,过滤并减压浓缩后获得膏状丹参粗提物;
(2)将膏状丹参粗提物经过纯化处理得到膏状丹酚酸B粗提物;所述纯化处理采用沉淀、萃取、大孔树脂层析、正向色谱或反向色谱;
(3)丹酚酸B成盐:将膏状丹参粗提物或膏状丹酚酸B粗提物溶于乙酸乙酯和无水乙醇的混合溶液,得到丹酚酸B粗溶液,在缓慢搅拌下滴加成盐剂或先加入抗坏血酸或亚硫酸氢钠,再缓慢搅拌滴加成盐剂,成盐pH为3-4,成盐温度为25-45℃,析出沉淀丹酚酸B盐;所述丹酚酸B粗溶液中丹酚酸B的重量百分比含量为5~80%,成盐剂的摩尔量为丹酚酸B摩尔量的1-2.5倍,成盐剂的浓度为0.1~10mol/L;
成盐剂的成盐组分为乙酸钠、丁酸钠、异辛酸钠、异辛酸钾、异辛酸钙、异辛酸四乙铵、碳酸钠、碳酸氢钠、碳酸铵、碳酸氢铵、醋酸铵、醋酸四乙铵、氨气、肼、三乙胺、二乙胺或乙二胺中的一种或两种;
(4)将丹酚酸B盐经酸析脱盐法、萃取脱盐法或大孔树脂层析脱盐法脱盐,干燥后获得高纯度的丹酚酸B。
2.根据权利要求1所述的一种采用盐析制备高纯度丹酚酸B的方法,其特征在于:所述酸析脱盐法为:将丹酚酸B盐溶于有机溶液,在搅拌下滴加浓度范围为0.1~10mol/L的醋酸、盐酸、磷酸或硫酸,使丹酚酸B盐转化为丹酚酸B留在有机溶液中,而醋酸、盐酸、磷酸或硫酸则成盐析出,过滤再将有机溶液浓缩;所述萃取脱盐法为:将酸化丹酚酸B盐溶于水,酸化使丹酚酸B盐转化为丹酚酸B后,将丹酚酸B由水相萃入乙酸乙酯相,再将乙酸乙酯相浓缩;所述大孔树脂层析脱盐法为:将丹酚酸B盐溶于水,酸化后丹酚酸B盐转化为丹酚酸B,上大孔树脂层析柱,水洗至中性后,再用乙醇将丹酚酸B洗脱,浓缩。
3.根据权利要求1所述的一种采用盐析制备高纯度丹酚酸B的方法,其特征在于:所述抗坏血酸或亚硫酸氢钠的用量为2~10g/l。
4.根据权利要求1所述的一种采用盐析制备高纯度丹酚酸B的方法,其特征在于:所述丹酚酸B成盐的过程在惰性气体保护下完成,所述惰性气体选自氮气、二氧化碳、氦气、氩气或氖气。
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CN101186572B (zh) * | 2007-12-19 | 2010-05-19 | 天津大学 | 从丹参水提取液中一步分离纯化丹酚酸的方法 |
CN102532077B (zh) * | 2012-01-06 | 2014-05-14 | 中山大学 | 一种快速制备色谱分离制备丹酚酸b的方法 |
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