CN103145654A - Docetaxel semi-synthesis method - Google Patents
Docetaxel semi-synthesis method Download PDFInfo
- Publication number
- CN103145654A CN103145654A CN2013101253008A CN201310125300A CN103145654A CN 103145654 A CN103145654 A CN 103145654A CN 2013101253008 A CN2013101253008 A CN 2013101253008A CN 201310125300 A CN201310125300 A CN 201310125300A CN 103145654 A CN103145654 A CN 103145654A
- Authority
- CN
- China
- Prior art keywords
- docetaxel
- side chain
- hydroxyl
- baccatin iii
- product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a docetaxel semi-synthesis method. Specifically, the docetaxel semi-synthesis method comprises the following steps: (1) performing united protection on 7-hydroxyl and 10-hydroxyl of 10-deacetylbaccatin III by using silane protecting group; (2) under solvent environment, performing condensation on the protected beta-lactam side chain precursor of 2-hydroxyl and the protected 10-deacetylbaccatin III; and (3) deprotecting the condensation product to produce crude docetaxel product, and purifying. In addition, the selection of reaction agents can be optimized, and the protection from strong acid and strong base and inert gas can be avoided, so that reaction equipment is simplified, the yield of the product is improved, and the synthesis cost is lowered.
Description
Technical field
The present invention relates to a kind of method take 10-deacetylate baccatin III as the semi-synthetic docetaxel of raw material.
Background technology
Cancer is one of primary cause of the death in the whole world.Estimate as not intervening, will have 8,400 ten thousand people to die from cancer during 2005 to 2015 according to World Health Organization.Therefore, the universe is always for to the anticancer unremitting effort.And in the treatment of cancer, pharmacological agent is an extremely important link, uses effective cancer therapy drug, will obtain longer survival time for the patient, has the hope of living on.According to statistics, in numerous antitumor drugs, the proportion maximum that the natural phant series antineoplastic medicament is shared has occupied the share over 27%.In the antitumour drug of front 10 of single product rank, the plant antitumour drug has occupied two seats, is taxol and docetaxel.Yet, still have in the market 90% taxol to come from plant extract, be limited to the Chinese yew genus plants poor growth, the reason such as population density is little, and the self-reproduction degree is low, the price of taxol is always high, and output does not catch up with huge demand fully yet.Therefore, the 10-deacetylate baccatin III abundanter by content in plant resources is the semisynthetic docetaxel of raw material, more and more comes into one's own.
Docetaxel (claims again Docetaxel; Docetaxel; DOC; docetaxel etc.) be French Rhone-Poulenc Rorer (Rhone-Poulenc-Rorer) and French National Nature research establishment (CNRS) in 1985 first with 10-deacetylate baccatin III as the parent nucleus skeleton, be synthesized by semisynthetic method.Docetaxel is considered to up to now curative effect one of the most significant cancer therapy drug.Phase late 1990s, it passes through clinical trial successively at aspects such as mammary cancer, lung cancer, cancer of the stomach, colorectal carcinomas, confirms to begin for clinical through FDA in 1996.A large number of experiments show that leukemia and anti entity tumour that it has wide spectrum are active, and lung cancer, skin carcinoma and head-neck malignant tumor are also had extremely strong antitumour activity.In addition, find in clinical study, docetaxel inhibition microtubule depolymerization, the ability that promotes the microtubule dimer to aggregate into microtubule are 2 times of taxol.As if on identical binding site, docetaxel and taxol exist competition, but the affinity of docetaxel is 2 times of taxol.In the Anticancer Activity in vitro test, confirmed that the docetaxel activity can reach 10 times of taxol.Therefore, explore the method for better suitability for industrialized production docetaxel and obtain the focus that active better new generation anti-cancer medicament becomes research by structural modification.
The chemical structural formula of docetaxel as shown in Figure 1, its chemical structure is very similar with taxol, distinguishes the C into the docetaxel parent nucleus
10The position is hydroxyl, side chain C
3 'The position is the N-tertbutyloxycarbonyl, and the N-benzoyl is replaced.The molecular formula of docetaxel is C
13H
53NO
14, relative molecular weight is 807.35, is white or broken white meal.The systematic naming method of docetaxel is 5 β, 20-epoxy-1 β, 2 α, 4 α, 7 β, 10 β, 13 α-hexahydroxy-Taxan-11 alkene-9-ketone-4-acetic ester-2-benzoic ether-13-[(2 ' R, 3 ' S)-N-tertbutyloxycarbonyl-3 '-phenylisoserine ester].
Docetaxel is not naturally occurring, and having been reported is substantially all to prepare in artificial semisynthetic mode.The main mode of production is take 10-deacetylate baccatin III as initial feed at present; after protection on 7,10 hydroxyls; optionally 13 hydroxyls are docked with the chiral side chain for preparing, obtain the docetaxel with blocking group, then deprotection obtains docetaxel.
Yang Xiaolong etc. apply for a patent (CN1923826A) and disclose under protection of inert gas; with 10-deacetylate baccatin III and many west sides chain in the solvent of ethyl acetate; react under alkyl two silicon amido Role of lithiums; obtain the docetaxel with protection; temperature of reaction is 0-100 ℃, and the reaction times is 10-60 hour, after reaction finishes; with the alkali in sour neutralization reaction, collect at last the docetaxel crude product.This technology belongs to early disclosed in patent report at home; has technically very large originality; has important reference significance; but this technology has been used rare gas element when hydroxyl adds protection; and also need low temperature environment in necessary situation, control relative difficult when industrial production, complicated to equipment requirements; and long reaction time has increased synthetic total cost greatly.
Chinese patent (CN101088994A) also discloses a kind of semisynthesis of docetaxel; the synthetic of side chain is by phenyl aldehyde and chloracetate, the α that the Darzens condensation reaction generates racemization to occur under base catalysis; the beta epoxide carboxylicesters; react through Rittertype again; reduction reaction, enzyme split and obtain optically pure oxazoline intermediate; reactive hydrogen on benzoyl, tertbutyloxycarbonyl protection nitrogen respectively, and hydrolysis of ester group again obtains side chain precursor, then obtains product with the parent nucleus condensation.The oxazole alkanes side chain precursor building-up process of using in this technology is simple, can be prepared by a lot of methods, really provide a good technology road for the semi-synthetic docetaxel of industrialization, but five-ring used herein difficulty when hydrolysis is larger, need to react under sourer condition, can the structure of docetaxel itself be constituted a threat under acidic conditions for a long time.
Patent (CN1931849A) also proposes 10-deacetylate baccatin III under the organic bases condition and chloroformic acid-(2 in addition; 2,2 ,-trichlorine) the upper protection of ethyl ester reaction; then under strong alkali environment with the side chain condensation, last acidic hydrolysis obtains docetaxel.In this route, other conventional steps remain is worth sure, but the reaction conditions of its condensation is too harsh, used highly basic, and under the highly basic condition, 10-deacetylate baccatin III easily decomposition can cause the loss of raw material, thereby improve reaction cost.
Summary is got up, and truly having of prior art is worth sure aspects in a large number, gets up to exist following shortcomings but sum up:
(1) severe reaction conditions needs rare gas element, and difficulty is relatively controlled in the requirements such as low temperature when industrial production, be difficult to realize industrialized production.
(2) selection for side chain is unreasonable, causes final hydrolysis requirement impacting than easy structure to product under acid environment.
(3) in some reaction scheme, when side chain and kernel condensation, require the condition of highly basic, yet parent nucleus raw material 10-deacetylate baccatin III is more responsive to highly basic.
Due to above shortcoming, the semi-synthetic cost of present docetaxel both domestic and external is high, and technology difficulty is large, and for overcoming above shortcoming, the present invention and aforesaid method difference are:
(1) selected suitable reaction solvent, and catalyzer, avoid using low temperature environment in reaction thereby make, be convenient to the control of reaction process, be fit to the semi-synthetic docetaxel of industrialization.
(2) all use relatively mild reaction reagent in whole synthetic route, avoided the protection of rare gas element, simplified conversion unit, thereby indirectly reduced synthetic cost.
(3) avoided as much as possible the use of strong acid and strong base in the reaction, avoided to greatest extent the loss of raw material and product, thereby improved the yield of sterling.
Summary of the invention
The semisynthesis that relates to a kind of docetaxel of the present invention; specifically in order to solve the too harsh problem of the synthetic middle reaction conditions of docetaxel, comprise and avoid using strong acid and strong base etc., optimize the selection of reaction reagent; thereby give up protection of inert gas; simplify conversion unit, reduce synthetic cost, secondly; further optimize on 7 of 10-deacetylate baccatin III and 10 hydroxyl protection methods; make the reaction times shorter, the condition milder, productive rate is higher.
Specifically comprise the following steps:
(1) the beta-lactam side chain precursor that the selection of many west sides chain precursor, the present invention have selected a large amount of patent documentations to propose, concrete synthetic method is with reference to existing document (CN94102895.X).
(2) use the protected silane bases to carry out Combined Protection to 7 of 10-deacetylate baccatin III and 10 hydroxyls; wherein the protected silane base comprises 1; 3-dichloro tetramethyl disiloxane, 1; two (Chlorodimethyl silylation) ethane, 1 of 2-; 5-dichloro hexam ethylcyclotrisiloxane, 1,7-dichloro octamethylcyclotetrasiloxane.
(3) under solvent environment, with 2 shielded beta-lactam side chain precursors of hydroxyl and shielded to the condensation of 10-deacetylate baccatin III, wherein solvent is tetrahydrofuran (THF).
(4) simply drip dilute hydrochloric acid and make the condensation product deprotection, generate the docetaxel crude product, and purifying.
Description of drawings
Fig. 1 is the structural formula of docetaxel
Fig. 2 is the semi-synthetic reaction formula of docetaxel
Embodiment
Further illustrate in the following embodiments the present invention, this does not limit the scope of the invention.
Embodiment 1 (semi-synthetic reaction formula is seen Fig. 2)
(1) hydroxyl protection of side chain precursor
3.4g is had optically active side chain precursor to be dissolved in 30ml tetrahydrofuran (THF) (THF), after slowly add successively 5.8g triethylamine, 76mg4-Dimethylamino pyridine (DMAP) and 2.4g β-(trimethyl silyl) ethoxyl methyl chlorine, mixture was stirred 30 minutes under 0 ℃.Put during this time plate, after being converted into the less product of polarity fully, add the dilution of 30mL ethyl acetate, rear with 15ml saturated sodium bicarbonate aqueous solution and the water washing of 15ml salt, and use the 5g dried over sodium sulfate, filter, filtrate is concentrated, and 50ml heptane recrystallization obtains white powder.The Büchner funnel vacuum filtration, and at room temperature vacuum-drying is to the 3.45g of constant weight, productive rate is 72%.
(2) side chain C
3 'Tertbutyloxycarbonyl is introduced in the position
Getting the product that has optically active after 0.95g back purifying is dissolved in the 10ml tetrahydrofuran (THF), after slowly add successively 1.1g triethylamine, 15mg DMAP and 5.04g tert-Butyl dicarbonate, mixture is at room temperature stirred, until no longer emit gas, during put plate, after being converted into the less product of polarity fully, add the dilution of 20ml heptane, and filter, and 30 ℃ of backspin inspissation contractings, until there is crystal to produce.The Büchner funnel vacuum filtration, with cold heptane recrystallization, and at room temperature vacuum-drying, to constant weight be 0.87g, productive rate is 65%.
(3) 7-OH of parent nucleus 10-deacetylate baccatin III, the protection of 10-OH
108.96g10-deacetylate baccatin III is dissolved in the 2.2L tetrahydrofuran (THF), then adds the DMAP of 61.08g.Add 42.67g1 in this solution, 3-dichloro tetramethyl disiloxane is observed by some plate, at room temperature until react completely, then with the DMAP-HCl salt that is precipitated out in reaction mixture, with the dilution of 2L heptane, and filters.Filter cake is dissolved in fully in 1: 1 mixed solvent system of 800ml ethyl acetate and normal heptane, reclaims to guarantee complete product.Drip the 14ml triethylamine in system, and concentrated, until there is crystal to produce.With mixture be cooled to 0 ℃ lower 30 minutes, crystallize out, the Büchner funnel vacuum filtration, with cold heptane recrystallization, with filter cake 50 ℃ of lower vacuum-dryings, to constant weight 109g.After filtered through silica gel, filtrate is concentrated, obtain second batch crystallization 13.2g.Total recovery is 122.2g, and productive rate is that 90%, HPLC purity is 99.2%.
(4) condensation of side chain and parent nucleus and deprotection
The 7-OH of parent nucleus 10-deacetylate baccatin III; the protection of 10-OH is to play hydroxyl protection with 1,3-dichloro tetramethyl disiloxane to do the used time, simply drips the dilute hydrochloric acid deprotection; obtain the crude product of docetaxel, then the productive rate after recrystallization is 79% from Virahol and heptane.
Embodiment 2
(1) hydroxyl protection of side chain precursor
3.4g is had optically active side chain precursor to be dissolved in the 30ml tetrahydrofuran (THF), after slowly add successively 5.8g triethylamine, 76mg4-Dimethylamino pyridine (DMAP) and 2.4g β-(trimethyl silyl) ethoxyl methyl chlorine, mixture was stirred 30 minutes under 0 ℃.Put during this time plate, after being converted into the less product of polarity fully, add the dilution of 30mL ethyl acetate, rear with 15ml saturated sodium bicarbonate aqueous solution and the water washing of 15ml salt, and use the 5g dried over sodium sulfate, filter, filtrate is concentrated, and 50ml heptane recrystallization obtains white powder.The Büchner funnel vacuum filtration, and at room temperature vacuum-drying is to the 3.45g of constant weight, productive rate is 72%.
(2) side chain C
3 'Tertbutyloxycarbonyl is introduced in the position
Getting the product that has optically active after 0.95g back purifying is dissolved in the 10ml tetrahydrofuran (THF), after slowly add successively 1.1g triethylamine, 15mg DMAP and 5.04g tert-Butyl dicarbonate, mixture is at room temperature stirred, until no longer emit gas, during put plate, after being converted into the less product of polarity fully, add the dilution of 20ml heptane, and filter, and 30 ℃ of backspin inspissation contractings, until there is crystal to produce.The Büchner funnel vacuum filtration, with cold heptane recrystallization, and at room temperature vacuum-drying, to constant weight be 0.87g, productive rate is 65%.
(3) 7-OH of parent nucleus 10-deacetylate baccatin III, the protection of 10-OH
0.544g10-deacetylate baccatin III is dissolved in the 10ml tetrahydrofuran (THF), then adds the DMAP of 0.4g.Add 0.22g1 in this solution, two (Chlorodimethyl silylation) ethane of 2-are observed by a plate, at room temperature until react completely, then with the DMAP-HCl salt that is precipitated out in reaction mixture, with the dilution of 20ml heptane, and filter.Filter cake is dissolved in fully in 1: 1 mixed solvent system of 20ml ethyl acetate and normal heptane, reclaims to guarantee complete product.Drip the 0.5ml triethylamine in system, and concentrated, until there is crystal to produce.With mixture be cooled to 0 ℃ lower 30 minutes, crystallize out, the Büchner funnel vacuum filtration, with 20ml cold heptane recrystallization, 50 ℃ of lower vacuum-dryings, to constant weight 0.58g, productive rate is 85% with filter cake.
(4) condensation of side chain and parent nucleus and deprotection
The 7-OH of parent nucleus 10-deacetylate baccatin III; the protection of 10-OH is to play hydroxyl protection and do the used time with two (Chlorodimethyl silylation) ethane of 1,2-, simply drips the dilute hydrochloric acid deprotection; obtain the crude product of docetaxel, then the productive rate after recrystallization is 77% from Virahol and heptane.
Embodiment 3
(1) hydroxyl protection of side chain precursor
3.4g is had optically active side chain precursor to be dissolved in the 30ml tetrahydrofuran (THF), after slowly add successively 5.8g triethylamine, 76mg4-Dimethylamino pyridine (DMAP) and 2.4g β-(trimethyl silyl) ethoxyl methyl chlorine, mixture was stirred 30 minutes under 0 ℃.Put during this time plate, after being converted into the less product of polarity fully, add the dilution of 30mL ethyl acetate, rear with 15ml saturated sodium bicarbonate aqueous solution and the water washing of 15ml salt, and use the 5g dried over sodium sulfate, filter, filtrate is concentrated, and 50ml heptane recrystallization obtains white powder.The Büchner funnel vacuum filtration, and at room temperature vacuum-drying is to the 3.45g of constant weight, productive rate is 72%.
(2) side chain C
3 'Tertbutyloxycarbonyl is introduced in the position
Getting the product that has optically active after 0.95g back purifying is dissolved in the 10ml tetrahydrofuran (THF), after slowly add successively 1.1g triethylamine, 15mg DMAP and 5.04g tert-Butyl dicarbonate, mixture is at room temperature stirred, until no longer emit gas, during put plate, after being converted into the less product of polarity fully, add the dilution of 20ml heptane, and filter, and 30 ℃ of backspin inspissation contractings, until there is crystal to produce.The Büchner funnel vacuum filtration, with cold heptane recrystallization, and at room temperature vacuum-drying, to constant weight be 0.87g, productive rate is 65%.
(3) 7-OH of parent nucleus 10-deacetylate baccatin III, the protection of 10-OH
0.544g10-deacetylate baccatin III is dissolved in the 10ml tetrahydrofuran (THF), then adds the DMAP of 0.3g.Add 0.28g1 in this solution, 5-dichloro hexam ethylcyclotrisiloxane is observed by some plate, at room temperature until react completely, then with the DMAP-HCl salt that is precipitated out in reaction mixture, with the dilution of 20ml heptane, and filters.Filter cake is dissolved in fully in 1: 1 mixed solvent system of 20ml ethyl acetate and normal heptane, reclaims to guarantee complete product.Drip the 0.5ml triethylamine in system, and concentrated, until there is crystal to produce.With mixture be cooled to 0 ℃ lower 30 minutes, crystallize out, the Büchner funnel vacuum filtration, with 20ml cold heptane recrystallization, 50 ℃ of lower vacuum-dryings, to constant weight 0.65g, productive rate is 87% with filter cake.
(4) condensation of side chain and parent nucleus and deprotection
The 7-OH of parent nucleus 10-deacetylate baccatin III; the protection of 10-OH is to play hydroxyl protection with 1,5-dichloro hexam ethylcyclotrisiloxane to do the used time, simply drips the dilute hydrochloric acid deprotection; obtain the crude product of docetaxel, then the productive rate after recrystallization is 76% from Virahol and heptane.
Claims (4)
1. the semisynthesis of a docetaxel is characterized in that comprising the following steps:
(1) use the protected silane bases to carry out Combined Protection to 7 of 10-deacetylate baccatin III and 10 hydroxyls;
(2) under solvent environment, with 2 shielded beta-lactam side chain precursors of hydroxyl and shielded to the condensation of 10-deacetylate baccatin III;
(3) make the condensation product deprotection, generate the docetaxel crude product, and purifying.
According to claim 1 described in method; it is characterized in that; the silicol protecting group of described 10-deacetylate baccatin III is 1; 3-dichloro tetramethyl disiloxane, 1; two (Chlorodimethyl silylation) ethane, 1 of 2-; 5-dichloro hexam ethylcyclotrisiloxane, 1,7-dichloro octamethylcyclotetrasiloxane.
According to claim 1 described in method, it is characterized in that, described solvent environment is tetrahydrofuran (THF).
According to claim 1 described in method, it is characterized in that, 2 hydroxyl protecting groups of described beta-lactam side chain precursor are β-(trimethyl silyl) ethoxyl methyl chlorine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101253008A CN103145654A (en) | 2013-04-12 | 2013-04-12 | Docetaxel semi-synthesis method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101253008A CN103145654A (en) | 2013-04-12 | 2013-04-12 | Docetaxel semi-synthesis method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103145654A true CN103145654A (en) | 2013-06-12 |
Family
ID=48544032
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013101253008A Pending CN103145654A (en) | 2013-04-12 | 2013-04-12 | Docetaxel semi-synthesis method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103145654A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1170292A2 (en) * | 1997-08-18 | 2002-01-09 | Florida State University | Process for selective derivatization of taxanes |
| US20030198594A1 (en) * | 1999-09-21 | 2003-10-23 | Collins Jerry M. | Imaging of drug accumulation as a guide to antitumor therapy |
| EP1183250B1 (en) * | 1999-05-28 | 2006-10-11 | Bristol-Myers Squibb Company | Semi-synthesis of paclitaxel using dialkyldichlorosilanes |
| CN101243061A (en) * | 2005-06-10 | 2008-08-13 | 佛罗里达州立大学研究基金有限公司 | Processes for the preparation of docetaxel |
| CN101468974A (en) * | 2007-12-28 | 2009-07-01 | 上海百灵医药科技有限公司 | Semi-synthesizing method for polyenic taxusol |
-
2013
- 2013-04-12 CN CN2013101253008A patent/CN103145654A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1170292A2 (en) * | 1997-08-18 | 2002-01-09 | Florida State University | Process for selective derivatization of taxanes |
| EP1183250B1 (en) * | 1999-05-28 | 2006-10-11 | Bristol-Myers Squibb Company | Semi-synthesis of paclitaxel using dialkyldichlorosilanes |
| US20030198594A1 (en) * | 1999-09-21 | 2003-10-23 | Collins Jerry M. | Imaging of drug accumulation as a guide to antitumor therapy |
| CN101243061A (en) * | 2005-06-10 | 2008-08-13 | 佛罗里达州立大学研究基金有限公司 | Processes for the preparation of docetaxel |
| CN101468974A (en) * | 2007-12-28 | 2009-07-01 | 上海百灵医药科技有限公司 | Semi-synthesizing method for polyenic taxusol |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5821263A (en) | Sulfenamide taxane derivatives | |
| RU2137764C1 (en) | Taxane derivatives, method of their synthesis, pharmaceutical composition and method of treatment | |
| AU2007309534B2 (en) | Process for making crystalline anhydrous docetaxel | |
| CN102417491B (en) | Method for preparing cabazitaxel by taking 10-deacetylate-baccatin III as raw material | |
| JPH05239044A (en) | New alkoxy substituted taxane and medicine composition containing the same | |
| JPH08502995A (en) | Furyl- or thienylcarbonyl-substituted taxane and pharmaceutical composition containing the same | |
| SK13712001A3 (en) | C7 ester substituted taxanes as antitumor agents | |
| CN103044395A (en) | Desloratadine-containing amino acid derivative as well as preparation method and application thereof | |
| AU3477797A (en) | 7-deoxy-6-substituted paclitaxels | |
| CN103145654A (en) | Docetaxel semi-synthesis method | |
| CN102180914A (en) | Preparation method of 2-deoxidizing-D-glucose | |
| JP2003527380A (en) | Simple and efficient hydrazinolysis of C-10 and C-13 ester functions of taxanes to give 10-DABIII | |
| CN114773356B (en) | Sesquiterpene derivative, pharmaceutical composition thereof, and preparation method and application thereof | |
| CN102887876B (en) | A kind of semisynthesis of Docetaxel of improvement | |
| CN101798294B (en) | Preparation method of anti-tumour medicine intermediate 10-deacetylbacctin III | |
| CN100417649C (en) | Preparation method of doxytasai | |
| CN101805339B (en) | Entecavir compound preparation method | |
| CN113620911A (en) | Paclitaxel derivative and preparation method thereof | |
| CN114644643A (en) | Twin drug and synthesis method and application thereof | |
| CN100406450C (en) | Synthesis process of polyene taxol | |
| CN109574830B (en) | Rosuvastatin calcium intermediate, and preparation method and application thereof | |
| CN108358923B (en) | Sophoridine pyrrole and indole derivatives, and preparation method and application thereof | |
| CN103044363B (en) | Paclitaxel derivative as well as preparation method and application thereof | |
| CN107365282B (en) | 10,13- of one kind, bis- branches-taxol preparation method | |
| CN115057845B (en) | Preparation method of arbeli |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130612 |