CN102020619A - Method for separating cephalomannine from taxol - Google Patents
Method for separating cephalomannine from taxol Download PDFInfo
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- CN102020619A CN102020619A CN 201010258652 CN201010258652A CN102020619A CN 102020619 A CN102020619 A CN 102020619A CN 201010258652 CN201010258652 CN 201010258652 CN 201010258652 A CN201010258652 A CN 201010258652A CN 102020619 A CN102020619 A CN 102020619A
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Abstract
The invention discloses a method for separating cephalomannine from taxol, which comprises the following steps: a, performing an 1,4-addition reaction, namely dissolving the mixture of taxol and cephalomannine in short-chain fatty alcohol, adding an organic alkali catalyst and stirring at room temperature; b, concentrating the solution, and performing separation by column chromatography to obtain a cephalomannine derivative and taxol; and c, dissolving the cephalomannine derivative, adding acidified active carbon, heating, refluxing, filtering, concentrating the filtrate, and recrystallizing to obtain cephalomannine. When the separation and purification method disclosed by the invention is used, the raw materials are cheap and readily available, the reaction and treatment conditions are mild, the product yield and purity are high, the separation of cephalomannine from taxol is facilitated considerably, and industrialization can be realized conveniently.
Description
Technical field
The present invention relates to a kind of chemical separation method, specifically be meant the separation method of two kinds of medicinal ingredientss.
Background technology
Taxol is the famous chemotherapeutic of the various metastatic tumours of treatment.It is used for the treatment of cancers such as ovarian cancer and mammary cancer by U.S. food and the approval of drug control department.
Taxol is a kind of natural compounds, is that extraction separation comes out in the Ramulus et folium taxi cuspidatae of the Pacific Ocean the earliest.The main at present raw material that extracts has european yew, Xizang Taxus chinensis, taxusyunnanensis, Northeast China Ramulus et folium taxi cuspidatae and southern china Ramulus et folium taxi cuspidatae.Taxol also can be by obtaining in vegetable cell suspension culture and the mould.
In various raw materials, the concentration of taxol is low especially, and for example in the yewtree skin, its content is between 0.0004-0.08% (weight ratio).From the so low raw material of content, it is very difficult that extraction and purifying provide the compound of clinical usefulness, introduce to the market unrealistic especially.
Cephalomannine is to have only the amide group side chain different on chemical structure with symbiotic a kind of natural Japanese yew alkyl compound of taxol and taxol.It can be used as the important source material of chemosynthesis taxol and Docetaxel, and can be as the precursor of novel taxane class exploitation.
Because with extremely similar in nature, the repeated multiple times separation is essential in structure for Cephalomannine and taxol.
Isolation of taxol having with non-chromatography method Cephalomannine reported.For example two keys on the side chain of Cephalomannine are carried out chemical improvement.Kingston etc. (J.Nat.Prod.55:NO.2,259-2,261[1992]) report for example, under the condition that osmium oxide (OsO4) exists, catalyzed oxidation Cephalomannine pendant double bonds obtains glycol, separates with taxol with chromatography and recrystallization method then.The problem of this method is that it can not adopt not purified taxanes mixture, because of the selectivity of two keys on the oxidation Cephalomannine side chain of osmium oxide too low.Osmium oxide has serious toxicity in addition, is not suitable for pharmaceutical industry, and this method can reduce the price of extraction and purge process greatly certainly.
In United States Patent (USP) (NOs.5334732 and 5336648 Murray etc.), introduced method with ozone oxidation Cephalomannine side chain.This method ozone oxidation crude extract will produce many reactions of taking place do not wished.Ozonolysis reactions is very strong and non-selectivity, and he can undesirable oxidizing reaction take place because of the many functional groups in taxol and the Cephalomannine.For example with the ketone in the taxol molecule, alcohol, reactions such as amine are perhaps with the two keys reactions on the taxane-ring of taxol and Cephalomannine.In addition, ozonizer equipment is also very expensive.
In Chinese patent (96193149.3 Pan Deyi etc.), introduced with the halogen addition on the Cephalomannine side chain, again by the isolating method of normal phase silicagel column.This method is relatively harsher to the conditional request of reaction, need be about 0-5 ℃, and lucifuge.And bromine has higher requirement as under the bigger situation of a kind of low-boiling point liquid halogen and toxicity for working condition.
Summary of the invention
The technical problem to be solved in the present invention is the defective that overcomes existing Cephalomannine and taxol separation method, and a kind of simple, economical and effective, treatment process that separation purity is high are provided.
In order to solve the problems of the technologies described above, the invention provides following technical scheme: the separation method of a kind of Cephalomannine and taxol may further comprise the steps:
A, 1,4-addition reaction: the mixture of taxol and Cephalomannine is dissolved in the short chain fatty alcohol, adds organic alkali catalyst, stirring at room; Further, short chain fatty alcohol comprises methyl alcohol, ethanol, Virahol; Organic bases catalyst pack is drawn together N-methylmorpholine, pyridine, 1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene; The mol ratio of Cephalomannine and organic alkali catalyst is 1: 0.075～0.125.
B, concentrated above-mentioned lysate, column chromatography for separation gets 3 "-alkoxyl group Cephalomannine derivative and taxol; Further, the moving phase of column chromatography is that ethyl acetate and sherwood oil volume ratio progressively increased to 2: 1 from 1: 1.
C, with 3 "-alkoxyl group Cephalomannine derivative dissolving, add the souring activity charcoal, reflux; Filter, filtrate concentrates after recrystallization gets Cephalomannine; Further, described souring activity charcoal refers to the activated carbon that concentrated nitric acid was handled; The solvent of described dissolving Cephalomannine derivative is a toluene; Recrystallization solvent is ethanol and water mixed liquid.
The Cephalomannine derivative content is greater than 98% (HPLC, area normalization method), and yield is higher than 95%.Content of taxol is higher than 20% (HPLC, external standard method), and yield is higher than 95%.Cephalomannine purity is higher than 98% (HPLC, external standard method), and yield is greater than 92%.
Separation purification method of the present invention is raw materials used cheap and easy to get, reaction and treatment condition gentleness, and product yield and purity height greatly facilitate Cephalomannine and are and the separating of taxol, and are convenient to realize industrialization.
Embodiment
Below the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein only is used for description and interpretation the present invention, and be not used in qualification the present invention.
Embodiment 1.
100g Cephalomannine and taxol mixture (containing taxol 9.2% respectively, Cephalomannine 61.9% (74mmol)) are dissolved in the 0.7L methyl alcohol, drip 1 of 90ml, 8-diazabicylo-dicyclo (5,4,0)-the 7-hendecene (contains 0.85g, methanol solution 5.55mmol).Stir after 30 minutes, concentrate.Cross silicagel column (1.5 kilograms of silica gel), moving phase ethyl acetate and sherwood oil gradient elution ratio progressively increased to 2: 1 by 1: 1.Get the 37.5g taxol, content 24.1%, yield 98.2%; Get 3 "-methoxyl group Cephalomannine derivative 62.3g, purity 99.8%, yield 98.9%.
Embodiment 2.
100g Cephalomannine and taxol mixture (containing taxol 7.2% respectively, Cephalomannine 77.3% (92.9mmol)) are dissolved in the 1.4L Virahol, drip 150mL and (contain 1.18g, N-methylmorpholine aqueous isopropanol 11.6mmol).Stir after 30 minutes, concentrate.Cross silicagel column (1.5 kilograms of silica gel), moving phase ethyl acetate and sherwood oil gradient elution ratio progressively increased to 2: 1 by 1: 1.Get taxol 22.6g, content 31.3% (8.3mmol), yield 98.2%; Get 3 "-isopropoxy Cephalomannine derivative 81.2g, yield 98.0%.
Embodiment 3.
The 100g edible activated carbon is added in 2 liters of concentrated nitric acids, with the ice-water bath cooling, stirs after 20 minutes in the adition process.Remove ice bath, use ultrasonoscope instead.Ultrasonic concussion is after 10 hours, filters and with 5 liters of washing leaching cakes of clear water washing.Filter cake is put into to vacuum drying oven under 60 ℃ temperature condition dry 24 hours.Then, gac that drying is good is stored in the airtight metal bottle by nitrogen protection.
Embodiment 4.
With 100g 3 "-methoxyl group Cephalomannine derivative (0.117mol) is dissolved in the 2L toluene, in being furnished with the reactor of water trap.The souring activity charcoal 5g. that adding embodiment 3 handles well is heated to 110 ℃ and fully refluxed 15 hours, filters.After filtrate concentrated yellow oil, oily matter is dissolved in the 700mL dehydrated alcohol, stir and add 600mL water down, to white flocks occurring.After-filtration got filter cake in static 12 hours, and washed three to four times with 13% aqueous ethanolic solution.Dry 93g white solid Cephalomannine (0.111mol), purity 99.8%, the yield 94.9% of getting.
It should be noted that at last: the above only is the preferred embodiments of the present invention, be not limited to the present invention, although the present invention is had been described in detail with reference to previous embodiment, for a person skilled in the art, it still can be made amendment to the technical scheme that aforementioned each embodiment put down in writing, and perhaps part technical characterictic wherein is equal to replacement.Within the spirit and principles in the present invention all, any modification of being done, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (8)
1. the separation method of Cephalomannine and taxol is characterized in that:
May further comprise the steps:
A, 1,4-addition reaction: the mixture of taxol and Cephalomannine is dissolved in the short chain fatty alcohol, adds organic alkali catalyst, stirring at room;
B, concentrated above-mentioned lysate, column chromatography for separation gets 3 "-alkoxyl group Cephalomannine derivative and taxol;
C, with 3 "-alkoxyl group Cephalomannine derivative dissolving, add the souring activity charcoal, reflux; Filter, filtrate concentrates after recrystallization gets Cephalomannine.
2. the separation method of Cephalomannine according to claim 1 and taxol is characterized in that: among the described step a, short chain fatty alcohol comprises methyl alcohol, ethanol, Virahol.
3. the separation method of Cephalomannine according to claim 1 and taxol is characterized in that: among the described step a, organic bases catalyst pack is drawn together N-methylmorpholine, pyridine, 1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene.
4. the separation method of Cephalomannine according to claim 1 and taxol is characterized in that: among the described step a, the mol ratio of described Cephalomannine and organic alkali catalyst is 1: 0.075～0.125.
5. the separation method of Cephalomannine according to claim 1 and taxol is characterized in that: among the described step b, the moving phase of column chromatography is that ethyl acetate and sherwood oil volume ratio progressively increased to 2: 1 from 1: 1.
6. the separation method of Cephalomannine according to claim 1 and taxol is characterized in that: among the described step c, described souring activity charcoal refers to the activated carbon that concentrated nitric acid was handled.
7. the separation method of Cephalomannine according to claim 1 and taxol is characterized in that: among the described step c, the solvent of described dissolving Cephalomannine derivative is a toluene.
8. the separation method of Cephalomannine according to claim 1 and taxol is characterized in that: among the described step c, recrystallization solvent is ethanol and water mixed liquid.
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| CN2010102586527A CN102020619B (en) | 2010-08-20 | 2010-08-20 | Method for separating cephalomannine from taxol |
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| CN2010102586527A CN102020619B (en) | 2010-08-20 | 2010-08-20 | Method for separating cephalomannine from taxol |
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| CN102020619A true CN102020619A (en) | 2011-04-20 |
| CN102020619B CN102020619B (en) | 2012-02-15 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102250047A (en) * | 2011-08-26 | 2011-11-23 | 贺金凤 | More-stable taxol compound and medicament composition thereof |
| CN104422749A (en) * | 2013-09-04 | 2015-03-18 | 南京工业大学 | Method for separating and purifying paclitaxel and cephalomannine |
| CN113512015A (en) * | 2021-05-26 | 2021-10-19 | 上海卓鼎生物技术有限公司 | Method for industrially purifying cephalomannine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5334732A (en) * | 1992-07-02 | 1994-08-02 | Hauser Chemical Research, Inc. | Oxidation of cephalomannine with ozone in the presence of taxol |
| CN101307040A (en) * | 2007-05-14 | 2008-11-19 | 中国科学院大连化学物理研究所 | Method for separating and preparing paclitaxel |
-
2010
- 2010-08-20 CN CN2010102586527A patent/CN102020619B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5334732A (en) * | 1992-07-02 | 1994-08-02 | Hauser Chemical Research, Inc. | Oxidation of cephalomannine with ozone in the presence of taxol |
| CN101307040A (en) * | 2007-05-14 | 2008-11-19 | 中国科学院大连化学物理研究所 | Method for separating and preparing paclitaxel |
Non-Patent Citations (1)
| Title |
|---|
| 《中国医药工业杂志》 19971231 陈冲 等 紫杉醇生产新工艺研究 344-347 第28卷, 第8期 2 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102250047A (en) * | 2011-08-26 | 2011-11-23 | 贺金凤 | More-stable taxol compound and medicament composition thereof |
| CN102250047B (en) * | 2011-08-26 | 2013-06-05 | 贺金凤 | Preparation method of taxol compound |
| CN104422749A (en) * | 2013-09-04 | 2015-03-18 | 南京工业大学 | Method for separating and purifying paclitaxel and cephalomannine |
| CN113512015A (en) * | 2021-05-26 | 2021-10-19 | 上海卓鼎生物技术有限公司 | Method for industrially purifying cephalomannine |
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| CN102020619B (en) | 2012-02-15 |
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Address after: No.111, Qinxin Road, Donggang Town, Xishan District, Wuxi City, Jiangsu Province Patentee after: Wuxi Yeshan Pharmaceutical Co.,Ltd. Address before: 214000 red bean Industrial Park, Donggang Town, Xishan District, Jiangsu, Wuxi Patentee before: JIANGSU YEW PHARMACEUTICAL Co.,Ltd. |
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Address after: 111 Qinxin Road, Donggang Town, Xishan District, Wuxi City, Jiangsu Province, 214000 Patentee after: Wuxi yew Pharmaceutical Co.,Ltd. Address before: 111 Qinxin Road, Donggang Town, Xishan District, Wuxi City, Jiangsu Province, 214000 Patentee before: Wuxi Yeshan Pharmaceutical Co.,Ltd. |