CN103087013A - Paclitaxel preparation method - Google Patents
Paclitaxel preparation method Download PDFInfo
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- CN103087013A CN103087013A CN2011103321975A CN201110332197A CN103087013A CN 103087013 A CN103087013 A CN 103087013A CN 2011103321975 A CN2011103321975 A CN 2011103321975A CN 201110332197 A CN201110332197 A CN 201110332197A CN 103087013 A CN103087013 A CN 103087013A
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Abstract
The invention provides a paclitaxel preparation method, wherein a raw material 7-xylosyl-10-deacetyltaxol (10DAXT) is subjected to pretreatment conversion to obtain a paclitaxel mixture (the pretreatment steps comprise ozone oxidation, a C-7 site xylosyl removing reaction, a C-10 site acetyl introduction reaction, and the like), and the obtained paclitaxel mixture is subjected to column chromatography, recrystallization and other steps to obtain the paclitaxel pure product. With the method, the paclitaxel mixture derived from the 10DAXT can be effectively separated; and efficient, inexpensive and environmental protection paclitaxel preparation can be achieved, and an effective path suitable for industrial production is provided for complete yew resource utilization.
Description
Technical field
The invention belongs to the medicine industry field, relate to specifically a kind of high performance column chromatogram and crystallization technique of utilizing and separate the method for high-purity taxol from the 10DAXT converted product.
Background technology
Taxol (1) is a class diterpene compound, is widely used in the treatment of kinds of tumors as a clinical line medication.At present, the approach of production taxol mainly contains: ⑴ directly extracts taxol from Chinese yew; ⑵ extract from Chinese yew genus plants and be separated to the compound with taxol mother nucleus structure---and 10-removes acetyl Bakating III (writing a Chinese character in simplified form 10DAB, 2), then uses the semi-synthetic taxol of chemical process.
[0003]Except 10DAB, several Ramulus et folium taxi cuspidatae kinds (Yunnan in the extensive plantation of China, south, the China Ramulus et folium taxi cuspidatae) in branches and leaves, also a large amount of existence another kinds have the compounds of taxol mother nucleus structure, and namely 10-removes acetyl-7-wood sugar taxol (10DAXT) (3), and its content can reach 1 ‰ of plant dry weight, 5-10 times of (Planta Medica, 2008 for taxol; 74:773-779).The difference of this compound and taxol only is the many xylosyls in C-7 position; the C-10 position lacks an ethanoyl, if therefore remove the C-7 xylosyl by effective ways, and introduces ethanoyl at C-10; just can be translated into taxol, thereby reach the effective utilization to China's taxus resource.Therefore this technique will be one of indispensable technique in following taxol industry.
Utilize that in 10DAXT taxol biosynthesis technique, the path comprises: 10DAXT goes wood sugar to obtain 10-deacetyl taxol (10DAT) (4), and the 10DAT acetylize generates taxol.Existing a lot of report discloses the C-7 xylosyl and has removed (US5412116 at present; US6028206; US5856532; US6437154) and the C-10 ethanoyl introduce that (ZL 200710010742.2; ZL 200710010739.0) technology, but in these reports, the quality standard of corresponding Purification of Taxol scheme and the finished product is not proposed all.Owing to usually can following the taxanes xyloside compounds of other kinds in the 10DAXT of plant origin, remove acetyl-7-wood sugar Cephalomannine (10DAXC) as 10-, 10-removes acetyl-7-wood sugar taxol C(10DAXTC), both can participate in together reaction in the 10DAXT conversion process, final Cephalomannine and the taxol C of generating, these compounds are extremely similar with the taxol structure, and usual way is difficult to separate; In addition, owing to having adopted new raw material and novel process, will certainly introduce the impurity that did not occur in many existing techniques in its raw material and each step, therefore must adopt efficient separation means, could remove these impurity, guarantee that product meets the standards of pharmacopoeia of various countries.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of taxol, the method are a kind of methods that can effectively separate the taxol mixture that derives from 10-DAXT (being called for short 10DAXT), and the product of acquisition meets the standard of pharmacopoeia of each country.
A kind of preparation method of taxol, go acetyl Japanese yew (10DAXT) alcohol to transform through pre-treatment raw material 7-wood sugar-10-and obtain the taxol mixture, pre-treatment step comprises that ozone oxidation, C-7 position goes to xylosyl reaction, C-10 position to introduce the ethanoyl reaction, it is characterized in that: the taxol mixture that obtains is carried out column chromatography, re-crystallization step; Specific as follows:
the invention provides a kind of preparation method of taxol, raw material 10-DAXT (10DAXT) is transformed through pre-treatment obtain taxol mixture (pre-treatment step comprise ozone oxidation, C-7 position go to xylosyl reaction, C-10 position to introduce the steps such as ethanoyl reaction), the taxol mixture that obtains is carried out the steps such as column chromatography, recrystallization, specific as follows: the pre-treatment of (1) raw material: the 10DAXT material dissolution is in methyl alcohol, make the solution that concentration is 1-10 mg/ml, then pass into ozone, it is that per hour to pass into ozone amount be 0.1-10 g to every liter of reaction system that ozone passes into speed, temperature of reaction 10-40 degree, reaction times is 0.5-5 h, transformation efficiency reaches more than 98%, by processing, go acetyl-7-wood sugar Cephalomannine (being called for short 10DAXC) to be oxidized to the higher derivative of polarity the impurity 10-that contains in raw material, again after past wood sugar and acetylization reaction, this oxidation products generates the oxidation products of corresponding Cephalomannine, easily separate with taxol, above-mentioned sample after ozonize is carried out the C-7 position to be gone to xylosyl reaction and C-10 position to introduce ethanoyl to react.can carry out as follows: after reaction, sample concentration is to doing, ratio in 1:100 is dissolved in methyl alcohol: in chloroform (4:1), add appropriate sodium periodate and sulfuric acid (0.5 mol/L), both be 0.6:4:1 with the sample quality ratio, stir 15h under room temperature, use dichloromethane extraction 3 times after the reaction mixture dilute with water, be dissolved in again after evaporated under reduced pressure in appropriate methyl alcohol and acetum (50%), add rear 2 h that stir of hydrazine hydrate (being 0.4:1 with raw material volume mass ratio) under 50～60 ℃ again in reaction solution, the dilute with water reaction solution, use again twice of dichloromethane extraction reaction solution, concentrating under reduced pressure obtains the 10DAT product.Acetylization reaction can adopt following method: the 10DAT sample dissolution is in tetrahydrofuran solution; add successively cerous nitrate; diacetyl oxide; both the ratio with sample is respectively 1:5:10; add saturated sodium bicarbonate to extinguish reaction after 20 degree reaction 3h, add subsequently hydrogen peroxide (the dioxygen water yield account for total reaction system amount 20%), 20 degree reactions are after 5 hours; with ethyl acetate extraction reaction solution three times, the evaporate to dryness ethyl acetate obtains the taxol mixture mutually afterwards.(2) column chromatography: the taxol blend sample is carried out silica gel column chromatography, and moving phase is the mixed solvent of polar solvent and non-polar solvent, elution speed be 1-2 column volume/hour, the elutriant consumption is 5-15 column volume; (3) recrystallization: with the cut of column chromatography collection, concentrated evaporate to dryness, be dissolved in methyl alcohol, making concentration is 0.03-1 g/ml solution, then add wherein deionized water, adding the amount of deionized water is methyl alcohol: deionized water=0.5:1 ~ 2:1, and placement is spent the night, crystalline product gets pure product of paclitaxel through decompression drying again after filtering.
The preparation method of taxol provided by the invention, described raw material sources are in Chinese yew genus plants, and in raw material, 10DAXT content is between 10%-80%, 10-goes acetyl-7-wood sugar taxol C(to be called for short 10DAXTC) content be that≤10%, 7-wood sugar-10-removes acetyl Cephalomannine (be called for short 10DAXC) content what are 0.2%-20%.
The preparation method of taxol provided by the invention, the content 20%-80% of taxol in the taxol mixture that the pre-treatment of described raw material process obtains, the content of taxol C≤10%, the content of Cephalomannine≤0.2%.
The preparation method of taxol provided by the invention, in described step (2), silicagel column is dynamic axial compression column, silica gel granularity 200-800 order, blade diameter length ratio 1:1-1:5, the dress column pressure is 5-30 Mpa, dress post mode is dry method or wet method dress post, and the mass ratio of taxol blend sample and silica gel is 1:20-1:200.
The preparation method of taxol provided by the invention, non-polar solvent is methylene dichloride in described step (2), trichloromethane, in normal hexane one or more, polar solvent is ethyl acetate, in methyl alcohol one or more; The moving phase preferred system is ethanol/methylene or ethyl acetate/normal hexane system.
The preparation method of taxol provided by the invention, whether qualified judgment criteria of a kind of component that column chromatography is collected has also been proposed, namely observe the separating effect of taxol and taxol C, content of taxol is greater than 85% in collecting component, and during with taxol C content ratio 〉=100:0.2, be qualified product, can merge evaporate to dryness.
The content of pure product of paclitaxel 〉=99.5% in the preparation method of taxol provided by the invention, described step (3), all the other single foreign matter contents are all less than 0.1%.
The preparation method of taxol provided by the invention, in described step (1) ozone pass into speed be every liter of reaction system per hour to pass into ozone amount be 2-10 g, temperature of reaction 15-40 degree, the reaction times is 0.5-2.5 h.
The preparation method of taxol provided by the invention, in described step (2), silicagel column is dynamic axial compression column, silica gel granularity 300-800 order, blade diameter length ratio 1:2-1:5, the dress column pressure is 20-30 Mpa, dress post mode is dry method or wet method dress post, and the mass ratio of taxol blend sample and silica gel is 1:50-1:100.
Method of the present invention can be efficiently, the preparation taxol of cheap, environmental protection, provides an effective way that adapts to suitability for industrialized production for taking full advantage of taxus resource.
Description of drawings
Fig. 1 is the liquid chromatogram of ozonization raw material and product; Wherein: a. raw material color atlas, color atlas after the b. ozonization, chromatographic peak 1 is 10DAXC, chromatographic peak 2 is the 10DAXC oxidation products;
Fig. 2 is the liquid chromatogram of the finished product taxol, and wherein: chromatographic peak 1 is taxol, and content is 99.5%.
Embodiment
The following examples will be further described the present invention, but not thereby limiting the invention.
Embodiment 1:
Take 100g 10DAXT crude product and (contain 10% 10DAXT, 3.2% 10DAXC, 0.3% 10DAXTC), be dissolved in the 10L methanol solution, under 10 degree conditions, pass into wherein ozone and react, the speed of passing into is 100 g/h, react end in 30 minutes, the liquid phase result shows that the transformation efficiency of 10DAXC reaches 99%.
Embodiment 2:
Take 100g 10DAXT crude product and (contain 50% 10DAXT, 10% 10DAXC, 7.5%10DAXTC), be dissolved in the 100L methanol solution, under 30 degree conditions, pass into wherein ozone and react, the speed of passing into is 50 g/h, react end in 50 minutes, the liquid phase result shows that the transformation efficiency of 10DAXC reaches 99.8%.
Embodiment 3:
Take 100g 10DAXT crude product and (contain 80% 10DAXT, 13% 10DAXC, 4%10DAXTC), be dissolved in the 20L methanol solution, under 40 degree conditions, pass into wherein ozone and react, the speed of passing into is 2 g/h, react end in 150 minutes, the liquid phase result shows that the transformation efficiency of 10DAXC reaches 99.5%.
Embodiment 4:
Take the taxol mixture material (containing 68% taxol, 3.1% taxol C, 0.11% Cephalomannine) that 100g is converted through 10DAXT, carry out column chromatography.Chromatographic column is axial compression column, internal diameter is 200mm, and silica gel granularity 300-400 order is poured 8kg silica gel in post into, pressure with 20Mpa is real with the pillar dress, moving phase is selected trichloromethane: methyl alcohol=98.5:1.5(volume ratio), carry out isocratic elution, collect the stream part that contains taxol, detect by liquid chromatography, obtain the 69.7g white solid after dividing the merging evaporate to dryness with qualified clusters, content of taxol is 87.9%, and yield is 76%.69.7g white solid is dissolved in 500ml methyl alcohol, drip wherein the 250ml deionized water, the room temperature hold over night, there are a large amount of white crystals to separate out, after filtering, (vacuum tightness-0.05Mpa) dry 12h obtains paclitaxel prodrugs 52.3g to 50 degree vacuum, product is through liquid chromatogram measuring, and content of taxol reaches 99.5%, and all the other impurity are all less than 0.1%.
Embodiment 5:
Take the taxol mixture material (contain 20% taxol, 0.1% taxol C is without Cephalomannine) that 200g is converted through 10DAXT, carry out column chromatography.Chromatographic column is axial compression column, internal diameter is 200mm, and silica gel granularity 500-800 order is poured 10kg silica gel in post into, pressure with 30Mpa is real with the pillar dress, moving phase is selected normal hexane: ethyl acetate=1:1(volume ratio), carry out isocratic elution, collect the stream part that contains taxol, detect by liquid chromatography, obtain the 37.0g white solid after dividing the merging evaporate to dryness with qualified clusters, content of taxol is 93.5%, and yield is 86%.37.0g white solid is dissolved in 1200ml methyl alcohol, drip wherein the 2400ml deionized water, the room temperature hold over night, there are a large amount of white crystals to separate out, after filtering, (vacuum tightness-0.05Mpa) dry 12h obtains paclitaxel prodrugs 25.6g to 50 degree vacuum, product is through liquid chromatogram measuring, and content of taxol reaches 99.6%, and all the other impurity are all less than 0.1%.
Embodiment 6:
Take the taxol mixture material (containing 80% taxol, 4.8% taxol C, 0.16% Cephalomannine) that 50g is converted through 10DAXT, carry out column chromatography.Chromatographic column is axial compression column, and internal diameter is 200mm, and silica gel granularity 300-400 order adopts wet method dress post.Add the 10L methylene dichloride in 5kg silica gel, after stirring, pour in post, use the pressure of 5Mpa with the pillar compacting, moving phase is selected methylene dichloride: methyl alcohol=98.5:1.5(volume ratio), carry out isocratic elution, collection contains stream part of taxol, detects by liquid chromatography, qualified clusters is divided obtain the 36.8g white solid after merging evaporate to dryness, content of taxol is 91.4%, and yield is 84.0%.36.8g white solid is dissolved in 500ml methyl alcohol, drip wherein the 500ml deionized water, the room temperature hold over night, there are a large amount of white crystals to separate out, after filtering, (vacuum tightness-0.05Mpa) dry 12h obtains paclitaxel prodrugs 25.3g to 50 degree vacuum, product is through liquid chromatogram measuring, and content of taxol reaches 99.9%, and all the other impurity are all less than 0.1%.
Claims (9)
1. the preparation method of a taxol, the raw material 10-DAXT is transformed through pre-treatment obtain the taxol mixture, pre-treatment step comprises that ozone oxidation, C-7 position goes to xylosyl reaction, C-10 position to introduce the ethanoyl reaction, it is characterized in that: will carry out column chromatography, re-crystallization step through the taxol mixture that pre-treatment obtains; Specific as follows:
(1) ozone oxidation: the 10-DAXT material dissolution is in methyl alcohol, make the solution that concentration is 1-10 mg/ml, then pass into ozone, go acetyl-7-wood sugar Cephalomannine to be oxidized to the higher derivative of polarity, to be convenient to the separation of the finished product the impurity 10-that contains in raw material;
(2) column chromatography: adopt silica gel column chromatography to separate in the taxol mixture, moving phase is the mixed solvent of polar solvent and non-polar solvent, elution speed be 1-2 column volume/hour, the elutriant consumption is 5-15 column volume;
(3) recrystallization: with the cut of column chromatography collection, concentrated evaporate to dryness, be dissolved in methyl alcohol, making concentration is 0.03-1 g/ml solution, then add wherein deionized water, adding the amount of deionized water is methyl alcohol: deionized water=0.5:1 ~ 2:1, and placement is spent the night, crystalline product gets pure product of paclitaxel through decompression drying again after filtering.
2. according to the preparation method of the described taxol of claim 1, it is characterized in that: described raw material sources are in Chinese yew genus plants, and in raw material, 10-DAXT content is between 10%-80%, it is that to remove acetyl-7-wood sugar Cephalomannine content be 0.2%-20% to≤10%, 10-that 10-removes the content of acetyl-7-wood sugar taxol C.
3. according to the preparation method of the described taxol of claim 1, it is characterized in that: in described step (1) ozone pass into speed be every liter of reaction system per hour to pass into ozone amount be 0.1-10 g, temperature of reaction 10-40 degree, the reaction times is 0.5-5 h.
4. according to the preparation method of the described taxol of claim 1, it is characterized in that: the content 20%-80% of taxol in the taxol mixture in described step (1), the content of taxol C≤10%, the content of Cephalomannine≤0.2%.
5. according to the preparation method of the described taxol of claim 1, it is characterized in that: in described step (2), silicagel column is dynamic axial compression column, silica gel granularity 200-800 order, blade diameter length ratio 1:1-1:5, the dress column pressure is 5-30 Mpa, dress post mode is dry method or wet method dress post, and the mass ratio of taxol blend sample and silica gel is 1:20-1:200.
6. according to the preparation method of the described taxol of claim 1, it is characterized in that: non-polar solvent is methylene dichloride in described step (2), trichloromethane, in normal hexane one or more, polar solvent is ethyl acetate, in methyl alcohol one or more.
7. according to the preparation method of the described taxol of claim 1, it is characterized in that: the content of pure product of paclitaxel 〉=99.5% in described step (3), all the other single foreign matter contents are all less than 0.1%.
8. according to the preparation method of the described taxol of claim 3, it is characterized in that: in described step (1) ozone pass into speed be every liter of reaction system per hour to pass into ozone amount be 2-10 g, temperature of reaction 15-35 degree, the reaction times is 0.5-2.5 h.
9. according to the preparation method of the described taxol of claim 5, it is characterized in that: in described step (2), silicagel column is dynamic axial compression column, silica gel granularity 300-400 order, blade diameter length ratio 1:2-1:5, the dress column pressure is 20-30 Mpa, dress post mode is dry method or wet method dress post, and the mass ratio of taxol blend sample and silica gel is 1:50-1:100.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418542A (en) * | 2015-11-17 | 2016-03-23 | 重庆臻源红豆杉发展有限公司 | Crystallization purification method for low-content and low-purity taxol crude product |
| CN109384749A (en) * | 2018-12-26 | 2019-02-26 | 重庆市碚圣医药科技股份有限公司 | A kind of purification process of taxol |
Citations (5)
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| US5334732A (en) * | 1992-07-02 | 1994-08-02 | Hauser Chemical Research, Inc. | Oxidation of cephalomannine with ozone in the presence of taxol |
| US5367086A (en) * | 1992-03-13 | 1994-11-22 | University Of Florida | Process for the preparation of taxol and 10-deacetyltaxol |
| CN1240789A (en) * | 1999-05-28 | 2000-01-12 | 复旦大学 | Process for purifying taxol with ozone |
| CN1458151A (en) * | 2003-05-26 | 2003-11-26 | 复旦大学 | Process for preparing high purity taxol by column bromating method |
| CN101503396A (en) * | 2009-03-04 | 2009-08-12 | 沈阳天峰生物工程技术有限公司 | Semisynthesis of paclitaxel |
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2011
- 2011-10-28 CN CN201110332197.5A patent/CN103087013B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5367086A (en) * | 1992-03-13 | 1994-11-22 | University Of Florida | Process for the preparation of taxol and 10-deacetyltaxol |
| US5334732A (en) * | 1992-07-02 | 1994-08-02 | Hauser Chemical Research, Inc. | Oxidation of cephalomannine with ozone in the presence of taxol |
| CN1240789A (en) * | 1999-05-28 | 2000-01-12 | 复旦大学 | Process for purifying taxol with ozone |
| CN1458151A (en) * | 2003-05-26 | 2003-11-26 | 复旦大学 | Process for preparing high purity taxol by column bromating method |
| CN101503396A (en) * | 2009-03-04 | 2009-08-12 | 沈阳天峰生物工程技术有限公司 | Semisynthesis of paclitaxel |
Non-Patent Citations (1)
| Title |
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| JEFFT,ET AL.: "An Improved Method for Separating Paclitaxel and Cephalomannine Using Ozone and Girard Reagents", 《J.ORG.CHEM》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418542A (en) * | 2015-11-17 | 2016-03-23 | 重庆臻源红豆杉发展有限公司 | Crystallization purification method for low-content and low-purity taxol crude product |
| CN109384749A (en) * | 2018-12-26 | 2019-02-26 | 重庆市碚圣医药科技股份有限公司 | A kind of purification process of taxol |
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Effective date of registration: 20180301 Address after: 215600 A 207 room A building center of Zhangjiagang Free Trade Zone, Suzhou Free Trade Zone, Jiangsu Patentee after: Zhangjiagang Institute of industrial technology, Dalian Institute of Chemical Physics, China Academy of Sciences Address before: 116023 Zhongshan Road, Liaoning, No. 457, Patentee before: Dalian Institute of Chemical Physics, Chinese Academy of Sciences |
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