WO2019144888A1 - 一种制备中乌宁的方法及其相关中间体 - Google Patents

一种制备中乌宁的方法及其相关中间体 Download PDF

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WO2019144888A1
WO2019144888A1 PCT/CN2019/072873 CN2019072873W WO2019144888A1 WO 2019144888 A1 WO2019144888 A1 WO 2019144888A1 CN 2019072873 W CN2019072873 W CN 2019072873W WO 2019144888 A1 WO2019144888 A1 WO 2019144888A1
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reduced pressure
under reduced
dichloromethane
water
ethanol
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PCT/CN2019/072873
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French (fr)
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王锋鹏
耿越飞
简锡贤
陈东林
耿福能
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好医生药业集团有限公司
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Priority to EP19743594.4A priority Critical patent/EP3744711B1/en
Priority to US16/963,973 priority patent/US11465971B2/en
Priority to KR1020207022930A priority patent/KR102518166B1/ko
Priority to JP2020562817A priority patent/JP6952206B2/ja
Publication of WO2019144888A1 publication Critical patent/WO2019144888A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the invention relates to the field of synthesis, in particular to a method for preparing mesaconine and related intermediates.
  • the Chinese medicine aconite is a processed product of the root of Aconitum carmichaeli Debx. It has the effect of returning to the sun, reversing the wind, cold and dampness, and warming and relieving pain (Chinese Pharmacopoeia, 2015 edition), as a famous Chinese medicine. Widely used in clinical practice.
  • Zhongning is the main cardiotonic active ingredient of aconite, as described in the following literature: Xiu-Xiu Liu, et al, Chem. Pharm. Bull, 2012, 60(1), 144-149; Xi- Xian Jian, et al, Nat. Prod. Commun, 2012, 7(6), 713-720; Chinese invention patent, 2012, CN102146057B; Zhong-Tang Zhang, et al, Nat. Prod. Commun, 2015, 10 ( 12), 2075-2084. Therefore, Zhongning has the prospect of developing anti-heart failure drugs.
  • Chinese invention patent CN 102146057B discloses a preparation method of Zhongwuing, which is made from aconitine of Aconitum soongaricum Stapf., is peracetylated, N-deethylated, N - Methylation and hydrolysis to obtain Zhongwuing.
  • this preparation method involves the highly toxic aconitine and mesaconitine, which is not conducive to safe production.
  • the object of the present invention is to provide a preparation method of Zhongwuing, which is simple in operation, high in yield, environmentally friendly and non-polluting, and is suitable for industrial production.
  • the preparation method of the medium wuning of the invention comprises the following steps:
  • Aconitine (I) is dissolved in ethanol (for example, 95% ethanol), hydrolyzed by sodium hydroxide, concentrated under reduced pressure, and the residue is diluted with water, the impurity alkaloid is extracted by dichloromethane, and the aqueous solution is acidified with hydrochloric acid.
  • Ammonia or sodium hydroxide ethanol solution is adjusted to pH 11 ⁇ 12, concentrated to dryness under reduced pressure, the residue is dissolved in dichloromethane - ethanol (6: 1 to 12:1, preferably 9:1, V / V), filtered, filtrate Concentrated under reduced pressure to obtain aconitine (II);
  • Aconitine (II) is dissolved in pyridine, reacted with acetic anhydride, concentrated under reduced pressure to obtain a residue, diluted with water, alkalized with ammonia, extracted with dichloromethane, and then combined with methylene chloride, dried and concentrated. Separation by silica gel column chromatography to obtain 3,14,15-triacetylurethane base (III);
  • Aconitine (II) is reacted with acetic anhydride under the catalysis of p-toluenesulfonic acid, concentrated under reduced pressure, diluted with water, diluted with water, alkalized with ammonia, extracted with dichloromethane, combined with dichloromethane, dried and concentrated. Separation by silica gel column chromatography to obtain 3,8,13,14,15-pentaacetylurethane base (IV);
  • 3,8,13,14,15-pentaacetylaconine base (IV) is dissolved in glacial acetic acid, N-bromosuccinimide is added, stirred at room temperature, concentrated under reduced pressure to obtain a residue, and aqueous ammonia is added. Extracting with dichloromethane, combining dichloromethane extracts, drying and concentrating under reduced pressure to obtain N-desethyl-3,8,13,14,15-pentaacetyl-aconine base (VI);
  • N-desethyl-3,14,15-triacetylaconine base (V) is dissolved in tetrahydrofuran, adding formaldehyde aqueous solution and glacial acetic acid at room temperature, stirring at room temperature, adding NaBH(OAc) 3 , stirring is continued.
  • Add ammonia water (adjusted to pH 9-10), dilute with water, extract with dichloromethane, combine dichloromethane extract, wash with water, dry and concentrate under reduced pressure to obtain 3,14,15-triacetyl (VII);
  • N-desethyl-3,8,13,14,15-pentaacetylaconine base is dissolved in tetrahydrofuran, adding formaldehyde aqueous solution and glacial acetic acid at room temperature, stirring at room temperature, adding NaBH(OAc) 3 , continue Stir, add ammonia water (adjusted to pH 9-10), dilute with water, extract with dichloromethane, combine dichloromethane extract, wash with water, dry and concentrate under reduced pressure to obtain 3,8,13,14,15 - pentaacetyl cumin (VIII);
  • the aconitine (I) can be prepared by the following method:
  • the root of the Aconitum plant is pulverized, and then extracted with a sulfuric acid-ethanol aqueous solution; the extract is concentrated under reduced pressure to obtain a solid extract; the solid extract is diluted with water, alkalized, extracted with ethyl acetate, and the solvent is recovered to obtain ethyl acetate.
  • the ester extract; the ethyl acetate extract is acid-soluble, filtered, and alkalized to obtain the aconitine (I).
  • the content of sulfuric acid may be 1-10 ⁇ based on the total mass of the aqueous solution of sulfuric acid-ethanol, and the content of ethanol may be 80-90%.
  • the content of sulfuric acid may be 5 ⁇ .
  • the content of ethanol can be 85%.
  • the Aconitum plant may be a Junggar aconite or a plurality of aconite.
  • Aconitine (II) is catalyzed by p-toluenesulfonic acid, and aconitine (II) is reacted with 6-8 mol of acetic anhydride under reflux for 3-4 hours. The residue is concentrated under reduced pressure, diluted with water and alkalized with ammonia. The mixture was extracted with dichloromethane, and the methylene chloride layer was combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography eluting with petroleum ether-acetone (10:1 to 2:1) to obtain 3,8,13 , 14,15-pentaacetyl aconitine (IV);
  • N-desethyl-3,14,15-triacetylaconine base (V) is dissolved in tetrahydrofuran, and stirred with 12 moles of 40% aqueous formaldehyde solution and 1-2 moles of glacial acetic acid at room temperature for 30 to 60 minutes.
  • Add 2 to 3 moles of sodium triacetoxyborohydride stir the reaction at room temperature for 30 to 60 minutes, adjust the concentrated ammonia to pH 9-10, dilute with water, extract with dichloromethane, and combine the dichloromethane extracts. Drying over anhydrous sodium sulfate and concentrating under reduced pressure to give 3,14,15-triacetyl-Nuanning (VII);
  • N-desethyl-3,8,13,14,15-pentaacetylaconine base is dissolved in tetrahydrofuran, and stirred with 12 moles of 40% aqueous formaldehyde solution and 1-2 moles of glacial acetic acid at room temperature 30-60 After a minute, add 2 to 3 moles of sodium triacetoxyborohydride, stir the reaction at room temperature for 30 to 60 minutes, adjust the concentrated ammonia to pH 9-10, dilute with water, extract with dichloromethane, and combine with dichloromethane extract. Drying over anhydrous sodium sulfate and concentrating under reduced pressure to give 3,8,13,14,15-pentaacetyl-Nuanning (VIII);
  • the invention also provides an intermediate used in the method for preparing the medium wuning, as follows:
  • the aconitine in the total alkaloid has certain toxicity, and the method of preparing the eugenin in the present invention obtains the non-toxic intermediate of the formula II by first hydrolyzing the benzoyl group in the aconitine (I) in the total alkaloid ( Aconitine), followed by acetylation, N-deethylation, N-methylation to obtain a non-toxic intermediate of formula III (3,14,15-triacetylurethane), intermediate IV (3,8,13,14,15-pentaacetylaconine base), intermediate of formula V (N-desethyl-3,14,15-triacetylurethane base), intermediate of formula VI ( N-desethyl-3,8,13,14,15-pentaacetylaconine base), intermediate of formula VII (3,14,15-triacetylneuron) and intermediate of formula VIII (3,8 , 13,14,15-penta-acetyl in Wuning), thus
  • Aconite plant Junggar aconit powder was sequentially extracted with 80 L, 36 L and 24 L times of 5 ⁇ 85% sulfuric acid 85% ethanol aqueous solution for 3 times, extracted for 2 hours each time, filtered, and the filtrate was combined;
  • Ethyl acetate was concentrated under reduced pressure to give 129 g of total alkaloid.
  • the content of aconitine in total alkaloids was determined by sampling HPLC.
  • the total amount of aconitine (I) in the total alkaloid was calculated from its content and wet weight to be about 42.5 g, and the yield was about 0.42%.
  • the aqueous layer was adjusted to pH 5 with concentrated aqueous hydrochloric acid, and then adjusted to pH 11-12 with dilute sodium hydroxide aqueous solution, and concentrated to dryness under reduced pressure to give a solid material (90 g), methylene chloride - anhydrous ethanol (9:1, V/) V) 900 ml, which was dissolved by heating, filtered, and the filtrate was concentrated under reduced pressure to give a solid material.
  • N-desethyl-3,14,15-triacetylaconine base (V) was dissolved in 25 ml of tetrahydrofuran, and 2 ml of 40% aqueous formaldehyde solution and 1 ml of glacial acetic acid were added at room temperature, and the temperature was kept at 30 °. After a minute, add 7.1 g (33.5 mmol) of NaBH(OAc) 3 , continue stirring for 30 minutes, adjust the concentrated ammonia to pH 9, dilute with 15 ml of water, extract twice with 20 ml of dichloromethane, and combine the extracts, then wash with water. After drying over anhydrous sodium sulfate, EtOAc (EtOAc m.)

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Abstract

本发明涉及制备中乌宁的方法及其相关中间体。具体地，本发明的制备中乌宁的方法以乌头属植物准噶尔乌头提取的乌头碱为原料经碱化、乙酰化、N-去乙基、N-甲基化和水解得到中乌宁。本发明的制备中乌宁的方法工艺简单，收率高，环保无污染，适合工业化生产。

Description

一种制备中乌宁的方法及其相关中间体 技术领域
本发明涉及合成领域，具体涉及制备中乌宁(mesaconine)的方法及其相关中间体。
背景技术
中药附子为毛茛科植物乌头(Aconitum carmichaeli Debx.)的子根的加工品，具有回阳救逆，逐风寒湿邪，温经止痛功效(中国药典，2015年版一部)，作为著名的中药广泛用于临床。
研究发现中乌宁是附子的主要强心活性成分，如在以下文献中有相关记载：Xiu-Xiu Liu，et al，Chem.Pharm.Bull,2012,60(1)，144-149；Xi-Xian Jian,et al,Nat.Prod.Commun,2012,7(6)，713-720；中国发明专利,2012年,CN102146057B；Zhong-Tang Zhang,et al,Nat.Prod.Commun,2015,10(12)，2075-2084。因此，中乌宁具有开发成抗心衰药物的前景。
中乌宁的化学名称为N-甲基-1α,6α,16β,18-四甲氧基-4-甲基-乌头-3α,8β,13β,14α,15α–五醇，分子式为C 24H 39NO 9，Cas No.：6792-09-2，具有如下结构式。
Figure PCTCN2019072873-appb-000001
中国发明专利CN 102146057B公开了中乌宁的制备方法，以分自乌头属植物准噶尔乌头(Aconitum soongaricum Stapf.)的乌头碱为原料，经全乙酰化，N-去乙基化，N-甲基化和水解得到中乌宁。然而，该制备方法涉及剧毒性的乌头碱(aconitine)和中乌头碱(mesaconitine)，不利于安全生产。
为了克服现有技术的不足，有必要开发一种操作简单、收率高、环保无污染、适合工业化的中乌宁的制备工艺。
发明内容
本发明的目的在于提供一种中乌宁的制备方法，该方法操作简单、收率高、环保无污染，适合工业化生产。
本发明的中乌宁的制备方法包括以下步骤：
1)将乌头碱(I)溶于乙醇(如，95％乙醇)，加入氢氧化钠水解，减压浓缩，残留物用水稀释，二氯甲烷萃除杂质生物碱，碱水液盐酸酸化，氨水或氢氧化钠乙醇溶液调至pH11～12，减压浓缩至干，残留物用二氯甲烷-乙醇(6:1至12:1，优选9:1，V/V)溶解，过滤，滤液减压浓缩，得乌头宁碱(II)；
Figure PCTCN2019072873-appb-000002
2)乌头宁碱(II)溶于吡啶中，与醋酐反应，减压浓缩得残留物，加水稀释，氨水碱化，二氯甲烷萃取，合并二氯甲烷层，依次经干燥，浓缩，硅胶柱层析分离，制得3,14,15-三乙酰乌头宁碱(III)；
Figure PCTCN2019072873-appb-000003
或者
乌头宁碱(II)在对甲苯磺酸催化下，与醋酐反应，减压浓缩得残留物，加水稀释，氨水碱化，二氯甲烷萃取，合并二氯甲烷层，依次经干燥，浓缩，硅胶柱层析分离，制得3,8,13,14,15-五乙酰乌头宁碱(IV)；
Figure PCTCN2019072873-appb-000004
3)3,14,15-三乙酰乌头宁碱(III)溶于冰醋酸中，加入N-溴代丁二酰亚胺，室温搅拌，减压浓缩得残留物，加入氨水，用二氯甲烷萃取，合并二氯甲烷萃取液，经干燥，减压浓缩，制得N-去乙基-3,14,15-三乙酰乌头宁碱(V)；
Figure PCTCN2019072873-appb-000005
或者
3,8,13,14,15-五乙酰乌头宁碱(IV)溶于冰醋酸中，加入N-溴代丁二酰亚胺，室温搅拌，减压浓缩得残留物，加入氨水，用二氯甲烷萃取，合并二氯甲烷萃取液，经干燥，减压浓缩，制得N-去乙基-3,8,13,14,15-五乙酰乌头宁碱(VI)；
Figure PCTCN2019072873-appb-000006
4)N-去乙基-3,14,15-三乙酰乌头宁碱(V)溶于四氢呋喃中，室温下加入甲醛水溶液和冰醋酸，室温搅拌，加入NaBH(OAc) 3，继续搅拌，加入氨水(调至pH9-10)，加水稀释后，用二氯甲烷萃取，合并二氯甲烷萃取液，依次经水洗，干燥，减压浓缩，制得3,14,15-三乙酰中乌宁(VII)；
Figure PCTCN2019072873-appb-000007
或者
N-去乙基-3,8,13,14,15-五乙酰乌头宁碱(VI)溶于四氢呋喃中，室温下加入甲醛水溶液和冰醋酸，室温搅拌，加入NaBH(OAc) 3，继续搅拌，加入氨水(调至pH9-10)，加水稀释后，用二氯甲烷萃取，合并二氯甲烷萃取液，依次经水洗，干燥，减压浓缩，制得3,8,13,14,15-五乙酰中乌宁(VIII)；
Figure PCTCN2019072873-appb-000008
5)3,14,15-三乙酰中乌宁(VII)或3,8,13,14,15-五乙酰中乌宁(VIII)溶于乙醇(如，95％乙醇)溶液中，加入氢氧化钠反应，盐酸调至pH4-5，再用氨水或氢氧化钠乙醇溶液调至pH9～12，滤去不溶物，减压浓缩，残留物用二氯甲烷-乙醇(6:1至12:1，优选9:1，V/V)溶解，抽滤，滤液减压浓缩，制得中乌宁(IX)
Figure PCTCN2019072873-appb-000009
在本发明的实施方案中，所述乌头碱(I)可以通过以下方法制备：
将乌头属植物的根粉碎后，加硫酸-乙醇水溶液回流提取；提取液减压浓缩，得固体提取物；固体提取物用水稀释，碱化后用醋酸乙酯萃取，回收溶剂，得醋酸乙酯提取物；醋酸乙酯提取物经酸溶、过滤、碱化沉淀，得所述乌头碱(I)。
在本发明的实施方案中，基于所述硫酸-乙醇水溶液的总质量，硫酸的含量可以为1-10‰，乙醇的含量可以为80-90％，优选地，硫酸的含量可以为5‰，乙醇的含量可以为85％。
在本发明的实施方案中，所述乌头属植物可以为准噶尔乌头或多根乌头。
更进一步地，本发明的中乌宁通过以下步骤制备获得：
1)将乌头属植物准噶尔乌头的根粉碎后，加5‰硫酸85％乙醇水溶液回 流提取；提取液减压浓缩，得固体提取物；固体提取物用水稀释，碱化后用醋酸乙酯萃取，回收溶剂，得醋酸乙酯提取物；醋酸乙酯提取物经酸溶、过滤、碱化沉淀，得总生物碱，其中总生物碱中主要成分为乌头碱(I)；
Figure PCTCN2019072873-appb-000010
2)将所述总生物碱溶于95％乙醇，加入所述总生物碱中乌头碱(I)总量的3～5倍摩尔量的氢氧化钠，室温反应1～2小时，减压浓缩除去95％乙醇，残留物用5～10倍量水稀释，二氯甲烷萃取除去杂质生物碱，碱水液用盐酸调至pH 5，氨水或氢氧化钠乙醇溶液调至pH11～12，减压浓缩至干，残留物用二氯甲烷-无水乙醇(9:1，V/V)溶解，过滤，滤液减压浓缩，得乌头宁碱(II)；
Figure PCTCN2019072873-appb-000011
3)乌头宁碱(II)溶于吡啶中，乌头宁碱(II)与6～8摩尔醋酐回流反应2-3小时，减压浓缩得残留物，加水稀释，氨水碱化，二氯甲烷萃取，合并二氯甲烷层，依次经无水硫酸钠干燥，浓缩，硅胶柱层析(二氯甲烷-乙醇＝200:1)分离，得3,14,15-三乙酰乌头宁碱(III)；
Figure PCTCN2019072873-appb-000012
或者
乌头宁碱(II)在对甲苯磺酸催化下，乌头宁碱(II)与6～8摩尔醋酐回流反应3-4小时，减压浓缩得残留物，加水稀释，氨水碱化，二氯甲烷萃取，合并二氯甲烷层，依次经无水硫酸钠干燥，浓缩，硅胶柱层析(石油醚-丙酮(10:1～2:1)洗脱)分离，得3,8,13,14,15-五乙酰乌头宁碱(IV)；
Figure PCTCN2019072873-appb-000013
4)3,14,15-三乙酰乌头宁碱(III)溶于10倍量冰醋酸中，与3～5摩尔的N-溴代丁二酰胺室温搅拌反应2-3小时，减压浓缩得残留物，浓氨水调至pH9～10，用二氯甲烷萃取2次，合并二氯甲烷萃取液，无水硫酸钠干燥，减压浓缩，得N-去乙基-3,14,15-三乙酰乌头宁碱(V)；
Figure PCTCN2019072873-appb-000014
或者
3,8,13,14,15-五乙酰乌头宁碱(IV)溶于10倍量冰醋酸中，与3～5摩尔的N-溴代丁二酰胺室温搅拌反应2-3小时,减压浓缩得残留物，浓氨水调至pH9～10，用二氯甲烷萃取2次，合并二氯甲烷萃取液，无水硫酸钠干燥，减压浓缩，得N-去乙基-3,8,13,14,15-五乙酰乌头宁碱(VI)；
Figure PCTCN2019072873-appb-000015
5)N-去乙基-3,14,15-三乙酰乌头宁碱(V)溶于四氢呋喃中，与12摩尔40％甲醛水溶液和1～2摩尔冰醋酸室温搅拌反应30～60分钟后，加入2～3摩尔 三乙酰氧基硼氢化钠，室温搅拌反应30～60分钟，浓氨水调至pH9-10，加水稀释后，用二氯甲烷萃取，合并二氯甲烷萃取液，依次经，无水硫酸钠干燥，减压浓缩，得3,14,15-三乙酰中乌宁(VII)；
Figure PCTCN2019072873-appb-000016
或者
N-去乙基-3,8,13,14,15-五乙酰乌头宁碱(VI)溶于四氢呋喃中，与12摩尔40％甲醛水溶液和1～2摩尔冰醋酸室温搅拌反应30～60分钟后，加入2～3摩尔三乙酰氧基硼氢化钠，室温搅拌反应30～60分钟，浓氨水调至pH9-10，加水稀释后，用二氯甲烷萃取，合并二氯甲烷萃取液，依次经无水硫酸钠干燥，减压浓缩，得3,8,13,14,15-五乙酰中乌宁(VIII)；
Figure PCTCN2019072873-appb-000017
6)3,14,15-三乙酰中乌宁(VII)或3,8,13,14,15-五乙酰中乌宁(VIII)用5％～10％氢氧化钠乙醇液水解，浓盐酸调至pH4-5，再用稀氢氧化钠乙醇溶液调至pH9～12，滤去不溶物，减压浓缩，残留物用二氯甲烷/无水乙醇(9:1,V/V)溶解，抽滤，滤液减压浓缩，得中乌宁(IX)
Figure PCTCN2019072873-appb-000018
本发明还提供了制备中乌宁的方法中使用的中间体，具体如下：
N-去乙基-3,14,15-三乙酰乌头宁碱，其结构式如式(V)所示
Figure PCTCN2019072873-appb-000019
N-去乙基-3,8,13,14,15-五乙酰乌头宁碱，其结构式如式(VI)所示
Figure PCTCN2019072873-appb-000020
3,14,15-三乙酰中乌宁，其结构式如式(VII)所示
Figure PCTCN2019072873-appb-000021
3,8,13,14,15-五乙酰中乌宁，其结构式如式(VIII)所示
Figure PCTCN2019072873-appb-000022
总生物碱中的乌头碱具有一定毒性，本发明的制备中乌宁的方法通过首先将总生物碱中的乌头碱(I)中的苯甲酰基水解得到无毒性的式II中间体(乌头宁碱)，再依次经乙酰化、N-去乙基、N-甲基化分别得到无毒性的式III中间体(3,14,15-三乙酰乌头宁碱)、式IV中间体(3,8,13,14,15-五乙酰乌头宁碱)、式V中间体(N-去乙基-3,14,15-三乙酰乌头宁碱)、式VI中间体(N-去乙基-3,8,13,14,15-五乙酰乌头宁碱)、式VII中间体(3,14,15-三乙酰中乌宁)和式VIII中间体(3,8,13,14,15-五乙酰中乌宁)，从而避免了毒性中间体的使用，保证生产 安全。本发明的中乌宁制备方法中使用的上述中间体不仅无毒性，而且使得工艺操作简单，纯化效果好。
具体实施方案
下列实施例进一步解释说明本发明，但是，它们并不构成对本发明范围的限制或限定。
实施例1乌头属植物准噶尔乌头总生物碱的提取
(1)取10kg乌头属植物准噶尔乌头干燥根，粉碎,过20目筛；
(2)乌头属植物准噶尔乌头粉末依次用其80L、36L和24L倍量的5‰硫酸85％乙醇水溶液回流提取3次，每次提取2小时，过滤，合并滤液；
(3)滤液减压浓缩，回收乙醇至流浸膏相对密度1.05～1.10，收集流浸膏0.46kg；
(4)流浸膏加1.4L水稀释，用氨水碱化，调至pH 10，放入萃取器中用乙酸乙酯萃取(2L×3次)，每次搅拌5～10分钟，收集萃取液；
(5)减压浓缩回收乙酸乙酯，得总生物碱129g。取样HPLC法测定总生物碱中乌头碱的含量。由其含量和湿重计算出总生物碱中乌头碱(I)的总量约为42.5g,收率约0.42％。
实施例2中乌宁的制备
(1)乌头宁碱(II)的制备
Figure PCTCN2019072873-appb-000023
取100g总生物碱(含乌头碱33g)用500ml 95％乙醇溶解后，加入7.2g(78mmol)氢氧化钠，室温下搅拌反应2小时，减压回收溶剂得120g固体物。固体物中加入1000ml水稀释后，用二氯甲烷萃取(500ml×2次)。水层用浓盐酸调至pH 5，再用稀氢氧化钠乙醇溶液调至pH11-12，减压浓缩至干，得 固体物90g，加入二氯甲烷-无水乙醇(9:1,V/V)900ml,加热溶解,过滤,滤液减压浓缩得固体物,得所需化合物22.5g。
收率:86％,白色无定形粉末,C 25H 41NO 9。
1H NMR(400MHz,CD 3OD)δ:0.99(3H,t,NCH2CH 3),3.15,3.20,3.25,3.50(各3H,s,4xOCH 3),3.59(1H,dd,J＝12.0,4.0Hz,H-3β),3.71(1H,d,J＝3.77(1H,d,J＝8.0Hz),4.09,(1H,d,J＝8.0Hz,H-15β),4.32(1H,d,J＝4.0Hz,H-14β)；
13C NMR(100MHz,CD 3OD)δ:13.8(q)，35.5(t)，38.8(t)，43.1(d)，44.5(s)，47.5(d)，48.3(t)，49.5(d)，50.1(t)，50.3(d)，51.1(s)，56.2(q)，58.2(q)，59.1(q)，61.6(q)，62.1(d)，70.7(d)，75.3(t)，77.7(s)，79.5(s)，79.7(d)，82.3(d)，84.2(d)，85.0(d)，93.1(d)；
ESI-MS m/z(％):500(100)[M+H] +。
(2)3,14,15-三乙酰乌头宁碱(III)的制备
Figure PCTCN2019072873-appb-000024
取10.0g(20mmol)乌头宁碱(II)与7.1g(70mmol)摩尔醋酐和100ml吡啶混合，在回流条件下反应2.5小时，减压浓缩得残留物，用170ml水稀释残留物，氨水碱化至pH9～10,二氯甲烷萃取(80ml×3)，合并萃取液，无水硫酸钠干燥，减压浓缩得固体物，硅胶柱层析，二氯甲烷-无水乙醇(200：1)洗脱，得所需化合物10.7g。
收率:85.6％,白色无定形粉末,C 31H 47NO 12。
1H NMR(400MHz,CDCl 3)δ:1.13(3H,t,J＝7.2Hz,NCH 2CH 3),2.06,2.07,2.18(各3H,s,3XOAc),3.20,3.23,3.27,3.56(各3H,s,4XOCH 3),4.65(1H,d,J＝5.2,H-14β),4.88(1H,t,J＝8.8Hz,H-3β),5.25(d,J＝6.0Hz,H-15β)；
13C NMR(100MHz,CDCl 3)δ:13.4(q),20.8(q),21.1(q),21.1(q),31.9(t),36.2(t),40.6(d),42.0(s),44.5(d),45.5(d),47.4(t),48.9(t),49.5(d),49.5(s),56.1(q), 57.8(q),58.7(q),60.6(d),61.3(q),71.4(d),71.7(t),74.3(s),76.5(s),78.6(d),81.7(d),82.8(d),87.2(d),88.3(d),170.1(s),170.9(s),173.3(s)；
ESI-MS m/z(％):626(100)[M+H] +。
(3)3,8,13,14,15-五乙酰乌头宁碱(IV)的制备
Figure PCTCN2019072873-appb-000025
取150mg(0.31mmol)乌头宁碱(II)溶于1mL醋酐中，室温搅拌下加入176mg(0.93mmol)对甲基苯磺酸。将反应液升温至120℃，反应3～4小时,减压浓缩蒸除大部分溶剂，所得残留液以20mL水稀释，5mL氨水调至pH 9～10,二氯甲烷萃取(10mL×2)，合并萃取液，无水硫酸钠干燥，抽滤，减压浓缩得残留液，硅胶柱层析分离，石油醚-丙酮(10:1～2:1)洗脱,得所需化合物161mg。
收率75％,白色无定形粉末,C 35H 51NO 14。
1H NMR(400MHz,CDCl 3)δ:1.14(3H,t,J＝7.2Hz,NCH 2CH 3),1.94(3H,s,OAc),2.04,2.08(各3H,s,2x OAc),2.10,2.13(各3H,s,2x OAc),3.19,3.21,3.25,3.33(各3H,s,4x OCH 3),4.05(1H,d,J＝6.0Hz,H-6β),4.84(1H,d,J＝5.2Hz，H-14β),4.88(1H,dd,J＝12.4,6.8Hz,H-3β),5.84(1H,d,J＝6.0Hz,H-15β)；
13C NMR(100MHz,CDCl 3)δ:13.5(q),21.1(q),21.1(q),21.2(q),21.3(q),22.0(q),31.9(t),36.0(t),41.1(d),42.1(s),43.7(d),45.0(d),45.5(d),47.0(t),48.8(t),49.8(s),56.1(q),58.7(q),58.8(q),60.3(q),61.0(d),71.2(t),71.3(d),76.3(d),78.2(d),80.7(s),81.4(d),83.7(d),88.2(d),88.8(s),168.4(s),169.6(s),170.2(s),170.3(s),170.7(s)；
ESI-MS m/z(％):710(100)[M+H] +。
(4)N-去乙基-3,14,15-三乙酰乌头宁碱(V)的制备
Figure PCTCN2019072873-appb-000026
取10.0g(17mmol)3,14,15-三乙酰乌头宁碱(III)，溶于100ml冰醋酸中，加入9.9g(66mmol)N-溴代丁二酰亚胺，室温搅拌反应2小时，减压浓缩得固体物，用少量二氯甲烷溶解，加入150ml水，浓氨水碱化至pH10，用二氯甲烷萃取(80ml×2)。合并萃取液，无水硫酸钠干燥，减压浓缩得10.5g固体物，硅胶柱层析，石油醚-丙酮(2：1)洗脱，得所需化合物6.4g。
收率:67.0％,白色无定形粉末,C 29H 43NO 12。
1H NMR(400MHz,CDCl 3)δ:2.05,2.08,2.27(各3H,s,3XOAc),3.24,3.25,3.29,3.57(各3H,s,4XOCH 3),4.68(1H,d,J＝4.8Hz,H-14β),5.09(1H,t,J＝6.4Hz,H-3β),5.25(1H,d,J＝6.4Hz,H-15β)；
13C NMR(100MHz,CDCl 3)δ:21.0(q),21.1(q),21.2(q),30.4(t),35.1(t),40.4(d),41.4(t),42.6(s),43.3(d),44.0(d),49.3(t),54.5(s),55.2(q),56.1(q),57.8(q),58.8(q),61.4(d),72.1(d),74.2(t),74.4(s),76.7(s),78.5(d),80.3(d),82.6(d),86.8(d),87.9(d),170.1(s),170.7(s),174.2(s)；
ESI-MS m/z(％):598(100)[M+H] +。.
(5)N-去乙基-3,8,13,14,15-五乙酰乌头宁碱(VI)的制备
Figure PCTCN2019072873-appb-000027
取10.0g(14mmol)3,8,13,14,15-五乙酰乌头宁碱(IV)，溶于100ml冰醋酸中，加入9.9g(66mmol)N-溴代丁二酰亚胺，室温搅拌反应2小时，减压浓缩得固体物，用少量二氯甲烷溶解，加入150ml水，浓氨水碱化至pH10，用二氯 甲烷萃取(80ml×2)。合并萃取液，无水硫酸钠干燥，减压浓缩得固体物8.5g。硅胶柱层析，石油醚-丙酮(2：1)洗脱，得所需化合物6.5g。
收率：67.7％，白色无定形粉末,C 33H 47NO 14。
1H NMR(400MHz,CDCl 3)δ:1.94(3H,s,OAc),2.03,2.07(各3H,s,2x OAc),2.14,2.16(各3H,s,2x OAc),3.22(3H,s,OMe),3.26(6H,s,2x OMe),3.32(3H,s,OMe),4.86(1H,d,J＝5.2Hz,H-14β),5.02(1H,dd,J＝9.6,5.6Hz,H-3β),5.84(1H,d,J＝6.0Hz,H-15β)；
13C NMR(100MHz,CDCl 3)δ：21.0(q),21.1(q),21.3(q),21.3(q),22.1(q),31.6(t),34.7(t),41.1(t),41.2(d),42.7(s),42.8(d),44.5(d),49.3(s),51.4(d),55.7(q),55.8(q),58.7(q),58.8(q),61.1(d),71.8(d),73.0(t),76.3(d),78.2(d),80.5(s),80.6(d),83.8(d),87.8(d),88.4(s),168.3(s),169.7(s),170.3(s),170.4(s),170.6(s)；
ESI-MS m/z(％):682(100)[M+H] +。
(6)3,14,15-三乙酰中乌宁(VII)的制备
Figure PCTCN2019072873-appb-000028
取10g(17mmol)N-去乙基-3,14,15-三乙酰乌头宁碱(V)溶于25ml四氢呋喃中，室温下加入2ml 40％甲醛水溶液和1ml冰醋酸，保持该温度搅拌30分钟后，再加入7.1g(33.5mmol)NaBH(OAc) 3，继续搅拌30分钟，浓氨水调至pH9，加15ml水稀释，用20ml二氯甲烷萃取2次，合并萃取液，依次用水洗，无水硫酸钠干燥，减压浓缩至干，得5.5g固体物，硅胶柱层析，氯仿-甲醇(9:1)洗脱，得所需化合物5.41g。
收率:53.1％,白色无定形粉末,C 30H 45NO 12。
1H NMR(400MHz,CDCl 3)δ:2.05,2.07,2.21(各3H,s,3XOAc),2.32(s,NCH 3),3.20,3.25,3.27,3.54(各3H,s,4XOCH 3),4.65(d,J＝3.2Hz,H-14β),4.88(t,J＝4.4Hz,H-3β),5.24(d,J＝6.0Hz,H-15β)；
13C NMR(100MHz,CDCl 3)δ:20.9(q),21.0(q),21.1(q),31.9(t),36.0(t),40.7(d),42.3(s),42.5(q),44.4(d),44.8(d),48.4(d),49.5(s),49.9(t),56.5(q),57.8(q),58.7(q),61.2(q),62.0(d),72.1(d),71.5(t),74.3(s),76.3(s),78.5(d),81.8(d),82.6(d),87.2(d),88.3(d),170.1(s),170.9(s),173.4(s)；
ESI-MS m/z(％):612(100)[M+H] +。
(7)3,8,13,14,15-五乙酰中乌宁(VIII)的制备
Figure PCTCN2019072873-appb-000029
取10g(14.6mmol)N-去乙基-3,8,13,14,15-五乙酰乌头宁碱(VI)溶于25ml四氢呋喃中，室温下加入2ml 40％甲醛水溶液和1ml冰醋酸，搅拌30分钟后，再加入7.1g(33.5mmol)NaBH(OAc) 3,继续搅拌30分钟，浓氨水调至pH 9,加15ml水稀释，用20ml二氯甲烷萃取2次。合并萃取液，依次用水洗，无水硫酸钠干燥，减压浓缩至干，得6.5g固体物。硅胶柱层析，氯仿-甲醇(9：1)洗脱，得所需化合物6.1g。
收率：59.8％，白色无定形粉末,C 34H 49NO 14。
1H NMR(400MHz,CDCl 3)δ：1.95(3H,s,OAc),2.04,2.08(各3H,s,2x OAc),2.14(6H,s,2x OAc),2.43(3H,s,NMe),3.19,3.23,3.26,3.33(各3H,s,4x OMe),4.06(1H,d,J＝6.4Hz,H-6β),4.86(1H,d,J＝5.2Hz,H-14β),4.90(1H,dd,J＝12.4,6.0Hz,H-3),5.83(1H,d,J＝6.0Hz,H-15β)；
13C NMR(100MHz,CDCl 3)δ：21.1(q),21.3(q),21.3(q),22.0(q),26.9(q),31.9(t),35.8(t),41.2(q),42.4(s),42.7(d),43.8(d),44.1(d),44.8(d),49.6(t),49.9(s),56.4(q),58.7(q),58.8(q),60.9(q),61.9(d),71.1(t),71.2(d),76.3(d),78.3(d),80.7(s),81.5(d),83.6(d),88.2(d),88.7(s),168.4(s),169.5(s),170.1(s),170.2(s),170.7(s)；
ESI-MS m/z(％):696(100)[M+H] +。
(8)中乌宁(IX)的制备
Figure PCTCN2019072873-appb-000030
方法1：由3,14,15-三乙酰中乌宁(VII)制备中乌宁(IX)
取10g(16.3mmol)3,14,15-三乙酰中乌宁(VII),溶于75ml 95％乙醇溶液中，加入2.29g(57.2mmol)氢氧化钠，回流反应30min。反应液冷却至室温，浓盐酸调至pH5，再用稀氢氧化钠乙醇溶液调至pH11～12。滤去不溶物，减压浓缩，得固体物。固体物用110ml二氯甲烷-无水乙醇(9:1，V/V)溶解，抽滤，滤液减压浓缩至干，得中乌宁7.22g，收率:91.1％。
方法2：由3,8,13,14,15-五乙酰中乌宁(VIII)制备中乌宁(IX)
取10g(14.4mmol)3,8,13,14,15-五乙酰中乌宁(VIII),溶于75ml 95％乙醇溶液中，加入2.29g(50.4mmol)氢氧化钠，回流反应30min。反应液冷却至室温，浓盐酸调至pH5，再用浓氨水调至pH9。滤去不溶物，减压浓缩得固体物9.5g。固体物用95ml二氯甲烷-无水乙醇(9:1，V/V)溶解，抽滤，滤液减压浓缩至干，得中乌宁6.2g，收率:90.0％。
上述中乌宁经光谱分析，具有如下理化特性：
中乌宁：白色固体，比旋度为
Figure PCTCN2019072873-appb-000031
分子式为C 24H 39NO 9；易溶于水、甲醇，溶于乙醇，微溶于异丙醇，极微溶于丙酮、氯仿。通过充分地二维核磁等光谱分析，确定其结构式为式(IX)
Figure PCTCN2019072873-appb-000032
中乌宁的光谱数据如下：
IR(KBr):3424cm -1，2932cm -1，2892cm -1，2821cm -1，1639cm -1，1453cm -1，1106cm -1；
1H NMR(400MHz,CDCl 3)δ:3.07(1H,dd,J＝8.4,6.0Hz,H-1β),3.75(1H,m,H-3β),4.15(d,J＝6,8Hz,H-6β),3,93(1H,d.J＝5.2Hz,H-14β),4.49)(1H,t,J＝5.6Hz,H-15β),3.19(1H,d,J＝6.0Hz,H-16),2.91(1H,s,H-17),3.65,3.74(各1H,ABq，J＝9.6Hz,H 2-18),2.48,2.79(各1H,ABq,J＝11.2Hz,H 2-19),2.34(3H,s，NCH 3),3.26(3H,s，OCH 3-1),3.34(3H,s,OCH 3-6),3.64(3H,s,OCH 3-16),3,32(3H,s,OCH 3-18)；
13C NMR(100MHz,CDCl 3)δ:82.6(C-1),33.8(C-2),71.5(C-3),43.4(C-4),46.5(C-5),83.2(C-6),46.4(C-7),78.8(C-8),48.8(C-9),41.6(C-10),50.1(C-11),36.9(C-12),76.3(C-13),78.7(C-14),81.5(C-15),90.7(C-16),62.5(C-17),76.8(C-18),49.8(C-19),42.5(NCH 3),56.3(OCH 3-1),57.9(OCH 3-6),61.3(OCH 3-16),59.1(OCH 3-18)；
ESI-MS m/z(％):486(100)[M+H] +；
HR-ESI-MS:准分子量测定值为486.2699，计算值为：486.2644。

Claims (9)

  1. 一种制备中乌宁的方法，包括以下步骤：
    1)将乌头碱(I)溶于乙醇，加入氢氧化钠水解，减压浓缩，残留物用水稀释，二氯甲烷萃除杂质生物碱，碱水液盐酸酸化，氨水或氢氧化钠乙醇溶液调至pH11～12，减压浓缩至干，残留物用二氯甲烷-乙醇溶解，过滤，滤液减压浓缩，得乌头宁碱(II)；
    Figure PCTCN2019072873-appb-100001
    2)乌头宁碱(II)溶于吡啶中，与醋酐反应，减压浓缩得残留物，加水稀释，氨水碱化，二氯甲烷萃取，合并二氯甲烷层，依次经干燥，浓缩，硅胶柱层析分离，制得3,14,15-三乙酰乌头宁碱(III)；
    Figure PCTCN2019072873-appb-100002
    或者
    乌头宁碱(II)在对甲苯磺酸催化下，与醋酐反应，减压浓缩得残留物，加水稀释，氨水碱化，二氯甲烷萃取，合并二氯甲烷层，依次经干燥，浓缩，硅胶柱层析分离，制得3,8,13,14,15-五乙酰乌头宁碱(IV)；
    Figure PCTCN2019072873-appb-100003
    3)3,14,15-三乙酰乌头宁碱(III)溶于冰醋酸中，加入N-溴代丁二酰亚胺，室温搅拌，减压浓缩得残留物，加入氨水，用二氯甲烷萃取，合并二氯甲烷萃取液，经干燥，减压浓缩，制得N-去乙基-3,14,15-三乙酰乌头宁碱(V)；
    Figure PCTCN2019072873-appb-100004
    或者
    3,8,13,14,15-五乙酰乌头宁碱(IV)溶于冰醋酸中，加入N-溴代丁二酰亚胺，室温搅拌，减压浓缩得残留物，加入氨水，用二氯甲烷萃取，合并二氯甲烷萃取液，经干燥，减压浓缩，制得N-去乙基-3,8,13,14,15-五乙酰乌头宁碱(VI)；
    Figure PCTCN2019072873-appb-100005
    4)N-去乙基-3,14,15-三乙酰乌头宁碱(V)溶于四氢呋喃中，室温下加入甲醛水溶液和冰醋酸，室温搅拌，加入NaBH(OAc) 3，继续搅拌，加入氨水，加水稀释后，用二氯甲烷萃取，合并二氯甲烷萃取液，依次经水洗，干燥，减压浓缩，制得3,14,15-三乙酰中乌宁(VII)；
    Figure PCTCN2019072873-appb-100006
    或者
    N-去乙基-3,8,13,14,15-五乙酰乌头宁碱(VI)溶于四氢呋喃中，室温下加入甲醛水溶液和冰醋酸，室温搅拌，加入NaBH(OAc) 3，继续搅拌，加入氨水，加水稀释后，用二氯甲烷萃取，合并二氯甲烷萃取液，依次经水洗，干燥，减压浓缩，制得3,8,13,14,15-五乙酰中乌宁(VIII)；
    Figure PCTCN2019072873-appb-100007
    5)3,14,15-三乙酰中乌宁(VII)或3,8,13,14,15-五乙酰中乌宁(VIII)溶于乙醇溶液中，加入氢氧化钠反应，盐酸调至pH4-5，再用氨水或氢氧化钠乙醇溶液调至pH9-12，滤去不溶物，减压浓缩，残留物用二氯甲烷-乙醇溶解，抽滤，滤液减压浓缩，制得中乌宁(IX)
    Figure PCTCN2019072873-appb-100008
  2. 根据权利要求1所述的方法，其中所述乌头碱(I)通过以下方法制备：
    将乌头属植物的根粉碎后，加硫酸-乙醇水溶液回流提取；提取液减压浓缩，得固体提取物；固体提取物用水稀释，碱化后用醋酸乙酯萃取，回收溶剂，得醋酸乙酯提取物；醋酸乙酯提取物经酸溶、过滤、碱化沉淀，得所述乌头碱(I)。
  3. 根据权利要求2所述的方法，其中基于所述硫酸-乙醇水溶液的总质量，硫酸的含量为1-10‰，乙醇的含量为80-90％。
  4. 根据权利要求2或3所述的方法，其中基于所述硫酸-乙醇水溶液的总质量，硫酸的含量为5‰，乙醇的含量为85％。
  5. 根据权利要求2所述的方法，其中所述乌头属植物为准噶尔乌头或多根乌头。
  6. N-去乙基-3,14,15-三乙酰乌头宁碱，其结构式如式(V)所示
    Figure PCTCN2019072873-appb-100009
  7. N-去乙基-3,8,13,14,15-五乙酰乌头宁碱，其结构式如式(VI)所示
    Figure PCTCN2019072873-appb-100010
  8. 3,14,15-三乙酰中乌宁，其结构式如式(VII)所示
    Figure PCTCN2019072873-appb-100011
  9. 3,8,13,14,15-五乙酰中乌宁，其结构式如式(VIII)所示
    Figure PCTCN2019072873-appb-100012
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Publication number Priority date Publication date Assignee Title
CN102146057A (zh) 2011-02-18 2011-08-10 四川大学 C19-二萜生物碱及其制备方法和以该化合物为活性成分的药物组合物及用途

Family Cites Families (7)

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DE19511235C2 (de) * 1995-03-27 1999-09-23 Klinge Co Chem Pharm Fab Verwendung von Aconitinen und Aconinen aus der Eisenhutknolle zur Prophylaxe einer echten Migräne
CN101759640B (zh) 2008-12-25 2012-02-29 上海中药制药技术有限公司 高纯度苯甲酰新乌头原碱的制备方法
CN102977020A (zh) 2012-12-05 2013-03-20 四川大学 乌头碱型生物碱及其制备方法和以该化合物为强心和抗心衰活性成分的药物组合物及用途
CN102973679B (zh) * 2012-12-21 2014-06-11 四川省中医药科学院 乌头属药材或其加工品中总生物碱提取物的制备方法
CN107445893A (zh) * 2017-08-31 2017-12-08 珠海润都制药股份有限公司 盐酸去甲乌药碱新晶型及其制备方法
CN108409657B (zh) * 2017-11-24 2021-08-20 孙益民 高纯高乌甲素及其制备方法
KR102528854B1 (ko) * 2018-01-24 2023-05-03 굿닥터 파머수티클 그룹 씨오., 엘티디. 메사코닌의 결정형 및 그의 제조방법

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102146057A (zh) 2011-02-18 2011-08-10 四川大学 C19-二萜生物碱及其制备方法和以该化合物为活性成分的药物组合物及用途

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 6792-09-2
See also references of EP3744711A4
WU, PING: "Study on Extraction, Isolation and Hydrolysis Law of Prepared Common Monkshood Branched Root Alkaloids", THESES OF CHENGDU UNIVERSITY OF TCM, 1 May 2007 (2007-05-01), pages 41, XP009522038 *
XIU-XIU LIU ET AL., CHEM. PHARM. BULL, vol. 60, no. 1, 2012, pages 144 - 149
XI-XIAN JIAN ET AL., NAT. PROD. COMMUN, vol. 7, no. 6, 2012, pages 713 - 720
YOSHISUKE TSUDA , OSMAN ACHMATOWICZ , LEO MARION : "Hypaconitine (Deoxymesaconitine) and Deoxyaconitine", JUSTUS LIEBIGS ANNALEN DER CHEMIE, vol. 680, 31 December 1964 (1964-12-31), pages 88 - 92, XP055718810, ISSN: 0075-4617, DOI: 10.1002/jlac.19646800111 *
ZHONG-TANG ZHANG ET AL., NAT. PROD. COMMUN, vol. 10, no. 12, 2015, pages 2075 - 2084
ZHOU, YUANPENG: "Detoxification of Prepared Common Monkshood Branched Root from the Hydrolysis of Diester-type Alkaloids (2)", PHARMACOLOGY AND CLINICS OF CHINESE MATERIA MEDICA, vol. 3, no. 30, 15 June 2014 (2014-06-15), pages 154 - 157, XP009522044, ISSN: 1001-859X *

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