CN101585780A - Method for asymmetric synthesis of chiral paclitaxel lateral chain - Google Patents

Method for asymmetric synthesis of chiral paclitaxel lateral chain Download PDF

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CN101585780A
CN101585780A CNA2009100530488A CN200910053048A CN101585780A CN 101585780 A CN101585780 A CN 101585780A CN A2009100530488 A CNA2009100530488 A CN A2009100530488A CN 200910053048 A CN200910053048 A CN 200910053048A CN 101585780 A CN101585780 A CN 101585780A
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compound
adds
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lateral chain
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胡文浩
钱宇
徐新芳
杨琍苹
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East China Normal University
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Abstract

The invention provides a method for asymmetric synthesis of chiral paclitaxel lateral chain, which relates to a method for synthesizing lateral chain of novel medicament anticancer paclitaxel. The method for asymmetric synthesis of chiral paclitaxel lateral chain (f) is carried out by using catalyst rhodium acetate and chiral Br phi nsted acid-p-diazonium-tert-butyl acetate (i), 2, 6-dybenal (ii), N-bezilidene-4-anisidine (iii) for unsymmetrical catalytic synthesis. After the reaction ends, single configuration intermediate product a (whose absolute configuration is identical to paclitaxel lateral chain) with two determined chiral centers separated by column chromatography method. And the paclitaxel lateral chain f is obtained by simply transforming protecting group for the structure of the intermediate product a. The method provided by the invention has the advantages of cheap and simply obtained raw material, good selectivity of catalyst for substrate, high optical purity of product, stable chemical property as well as easy storage and transportation.

Description

A kind of method of asymmetric synthesis chiral paclitaxel lateral chain
Technical field
A kind of method of asymmetric synthesis chiral paclitaxel lateral chain relates to a kind of synthetic method of side chain of effects of taxol, belongs to the synthesis technical field of effects of taxol.
Background technology
Taxol (Paclitaxel) commodity (Taxol) by name are safe plain.Structure is as shown in the figure:
Figure A20091005304800041
Taxol is a kind of Taxan diterpene-kind compound with unique antitumour activity of separation and Extraction from the bark of Chinese yew genus plants at first.The crude extract of promptly finding the yewtree trunk as far back as the sixties has anti-tumor activity, Wall in 1971 etc. therefrom separate obtain safe plain.National cancer institute is found it to ovarian cancer in the screening of the JEG-3 of vitro human, mammary cancer and large bowel cancer curative effect are outstanding, and transplanted animal tumor and melanoma, lung cancer are also had also the obvious suppression effect.Taxol enters clinical study in nineteen eighty-three.Because its unique mechanism of action is (by inducing and impelling tubulin polymerization to become microtubule, suppress the depolymerization of the microtubule that forms simultaneously, thereby cause the arrangement of microtubule fasolculus unusual, form aster, make cell when mitotic division, can not form normal mitotic spindle, thereby suppressed the division and the propagation of cell, cause the death of cell), effective to a lot of resistance patients, be considered to a kind of one of the most effective cancer therapy drug.
But two subject matters have in use appearred in Taxol: the one, water-soluble very poor (0.03mg/ml), be difficult to make appropriate formulation, bioavailability is lower: the 2nd, and content very low (the highest about 0.07%) in the plant of Taxus, taxol poor growth in addition, after peelling off, bark can not regenerate, trees are restricted the source death.At present, succeed by different routes in complete synthesis three laboratories by the U.S. of Taxol, yet because the synthesis step complexity, therefore the cost costliness does not still have industrial application value.It is found that afterwards can utilize from leaf of Japanese Yew, extract 102 to go acetyl baccatin III (102DAB) to carry out semi-synthetic, just can obtain taxol as long as in the 102DAB molecule, introduce chiral paclitaxel lateral chain f.France Potier etc. has reported that at first the semi-synthetic of taxol, Denis etc. by optionally protecting C-7 hydroxyl and esterification C-13 base, add the side chain of protection from the taxol parent nucleus then, removes protecting group just to obtain taxol, and total recovery can reach 55%.Because leaf of Japanese Yew can be adopted 4 times in 1 year, leaf can be regenerated again, so the 102DAB source is abundant, as long as a large amount of synthetic C13 side chain f just can obtain this cancer therapy drug by semisynthetic method.The method of taxol biosynthesis side chain f has multiple, but most synthesis step complexity, productive rate is lower, minority especially with the direct taxol biosynthesis side chain of asymmetry catalysis method, as document Shuj Kobayashi.et al J.Am.Chem.Soc.1998,120,431-432.But its severe reaction conditions (temperature of reaction＜-45 ℃), reaction raw materials also is not easy to obtain.
Summary of the invention
It is extensive to the purpose of this invention is to provide a kind of raw material sources, cheap, and the reaction conditions gentleness is simple to operate, has the synthetic method of the paclitaxel lateral chain of higher industrial value.
In order to achieve the above object; we are by screening catalyzer and substrate; obtained our the desired and corresponding to intermediate product a of paclitaxel lateral chain configuration; and the structure of gained intermediate product a carried out the conversion of simple protecting group; just can obtain paclitaxel lateral chain, and have higher optical purity.
The present invention with the diazoacetic acid tert-butyl ester (i), 2,6 Dybenals (ii), N-benzylidene-4-anisidine (iii) is raw material, with acetic acid rhodium and chirality
Figure A20091005304800051
Acid is directly carried out asymmetric synthesis for catalyzer to three components, and the intermediate product a that obtains carries out protecting group and transforms and just can obtain and the corresponding to product of paclitaxel lateral chain node configuration (as scheming) on chemical structure.
Figure A20091005304800052
Figure A20091005304800061
In the formula: PMP=p-methoxyphenyl, TBSCl=TERT-BUTYL DIMETHYL CHLORO SILANE, TBS=tertiary butyl dimethyl, DMF=N, N dimethyl formamide, CAN=ceric ammonium nitrate, Et 3The N=triethylamine, TBAF=tetrabutyl ammonium fluoride, THF=tetrahydrofuran (THF).
Concrete steps are as follows:
The 1st step, intermediate product (a) synthetic: at N 2Protection down, with raw material 2,6 Dybenals (ii), N-benzylidene-4-anisidine (iii), the catalyst acetic acid rhodium and
Figure A20091005304800062
Acid adds in the reaction flask, under-20 ℃～30 ℃, with peristaltic pump the diazoacetic acid tert-butyl ester (i) is added wherein, the diazoacetic acid tert-butyl ester (i) being added the back in 1～2 hour stirred 0.5～1 hour under the room temperature, obtain intermediate product (a), then with column chromatography method with intermediate product (a) separation and purification; The molar ratio of above-mentioned reaction is diazonium tert.-butyl acetate (i): 2,6 Dybenals (ii): N-benzylidene-4-anisidine (iii): the acetic acid rhodium:
Figure A20091005304800063
Acid=1～2: 1～2: 1～1.5: 0.005～0.05: 0.01～0.1;
The 2nd step, compound (b) synthetic: at N 2Protection down, (a) is dissolved in the methanol solution with intermediate product, adds Pd/C and ammonium formiate, stirring at room 12～24 hours, stop to stir, filter, use methanol wash Pd/C 3～5 times, add water washing after collection filtrate is spin-dried for, with ethyl acetate extraction 3～5 times, anhydrous sodium sulfate drying is spin-dried for and obtains white solid compound (b), and above-mentioned reaction molar ratio is intermediate product (a): Pd/C: ammonium formiate=1: 0.5～2: 5～10;
The 3rd step, compound (c) synthetic: at N 2Protection down, (b) is dissolved in N with compound, in the N dimethyl formamide solution, stir adding TERT-BUTYL DIMETHYL CHLORO SILANE and imidazoles down, stirred 12～15 hours under 20 ℃～40 ℃ temperature, add water washing, with ethyl acetate extraction 3～5 times, collect extraction liquid, use anhydrous sodium sulfate drying, be spin-dried for white solid compound (c), above-mentioned reaction molar ratio is compound (b): TERT-BUTYL DIMETHYL CHLORO SILANE: imidazoles=1: 1.5～2.5: 2.5～5;
The 4th step, compound (d) synthetic: at N 2Protection down; (c) is dissolved in the acetonitrile solution with compound; the acetonitrile solution that under ice bath, adds ceric ammonium nitrate; acetonitrile solution is by acetonitrile: water=3～5: 1 part of mass ratio is formed, and 0 ℃ is stirred down and adds saturated aqueous solution of sodium bicarbonate after 8～10 hours to regulate PH be 8～9, with this solution of ethyl acetate extraction 3～5 times; collect extraction liquid; use anhydrous sodium sulfate drying, be spin-dried for the orange that obtains and be dissolved in the dichloromethane solution, at N 2Protection adds triethylamine and Benzoyl chloride down, and stirring at room 3～4 hours is spin-dried for solvent, separates obtaining white solid compound (d) with column chromatography method; The molar ratio of above-mentioned reaction is compound (c): ceric ammonium nitrate: triethylamine: Benzoyl chloride=1: 3～5: 2～3: 1.5～2;
The 5th step, compound (e) synthetic: at N 2Protection is dissolved in compound (d) in the tetrahydrofuran solution down, adds tetrabutyl ammonium fluoride, and stirring at room 1～2 hour adds after the water washing with ethyl acetate extraction 3～5 times, and anhydrous sodium sulfate drying is collected filtrate and is spin-dried for and obtains white solid compound (e); The molar ratio of above-mentioned reaction is compound (d): tetrabutyl ammonium fluoride=1: 1.2～1.5;
The 6th step, target compound paclitaxel lateral chain (f) synthetic: at N 2Protection is dissolved in substrate compounds (e) in the dichloromethane solution down, adds trifluoracetic acid, and stirring at room 12～15 hours is spin-dried for solvent, adds ethyl acetate, separates out solid target thing (f), filters and obtains white solid target compound (f); The molar ratio of above-mentioned reaction is compound (e): trifluoracetic acid=1: 5～10.
Advantage of the present invention:
1. raw material of the present invention, diazoacetic acid fat can be made by natural amino acid (glycine and derivative a thereof) step, and pure and mild imines all can be buied on market, and wide material sources are cheap.
2. the present invention makes up baroque intermediate product a with a plurality of components by single step reaction, and can carry out chirality control by catalyzer, and the step that this has just shortened synthetic this compounds greatly meets the requirement of Atom economy and Green Chemistry.
3. synthetic intermediate product a of the present invention just can make the key intermediate of drug taxol by the conversion of simple protecting group, the reaction conditions gentleness, and experimental implementation is simple, has higher industrialization use value.
Embodiment
Below in conjunction with embodiment the present invention is done further narration.
Embodiment 1
Synthesizing of intermediate product (a)
At N 2Under the atmosphere, with 2,6 Dybenals (22mmol), N-Ben Yajiaji-4 p-methoxy-phenyl imines (20mmol), acetic acid rhodium (0.1mmol) and R-Binal phosphoric acid (0.4mmol) add methylene dichloride 20ml down at 0 ℃, with peristaltic pump the diazoacetic acid tert-butyl ester (22mmol) is joined in the reaction system of above-mentioned raw materials composition, time set is 1.5 hours.Added behind the diazoacetic acid tert-butyl ester stirring at room 0.5 hour, (ethyl acetate: normal hexane=1: 100～ethyl acetate: normal hexane=1: 20) separate and obtain intermediate product (a) product dr value 67:33ee value 88%, yield is 72% then to use column chromatography method.
Synthesizing of compound (b)
At N 2Under the atmosphere, (a) (5mmol) is dissolved in the 20ml methanol solution with intermediate product, adds 10%Pd/C (2.5g), ammonium formiate (20mmol), stirring at room 12 hours.Stop to stir, filter, use methanol wash Pd/C 3 times, add water 20ml washing after collection filtrate is spin-dried for, with ethyl acetate extraction (20ml*3), anhydrous sodium sulfate drying is spin-dried for and obtains white solid b 1.00g, and yield is 58%.In ethyl acetate: recrystallization obtains the product b 0.81g of ee＞99% in normal hexane=10: 1 solution.
Synthesizing of compound (c)
At N 2In the environment, compound (b) (2.5mmol) is dissolved in 5ml N, in the N dimethyl formamide solution, stirs adding TERT-BUTYL DIMETHYL CHLORO SILANE (3mol) and imidazoles (6mmol) down, stirred 12 hours under 30 ℃ of temperature, add the 10ml water washing, use ethyl acetate extraction 10ml*5, collect extraction liquid, use anhydrous sodium sulfate drying, be spin-dried for white solid c 1.06g,, yield 93%.
Synthesizing of compound (d)
At N 2Under the atmosphere, compound (c) (2mmol) is dissolved in the 5ml acetonitrile solution, acetonitrile solution (the 2ml) (acetonitrile: water=5: 1) that under ice bath, adds ceric ammonium nitrate (6mmol), 0 ℃ of following stirring adds saturated aqueous solution of sodium bicarbonate adjusting PH after 10 hours be 8～9, with ethyl acetate extraction (20ml*4), collect extraction liquid, use anhydrous sodium sulfate drying, select the dried orange that obtains to be dissolved in the 5ml dichloromethane solution, at N 2Add triethylamine (4mmol) and Benzoyl chloride (2.4mmol) in the environment, stirring at room 4 hours, be spin-dried for solvent, (ethyl acetate: normal hexane=1: 40～ethyl acetate: normal hexane=1: 10), yield is 45% to obtain compound (d) 0.32g with the column chromatography method separation.
Synthesizing of compound (e)
At N 2In the environment, compound (d) (0.8mmol) is dissolved in the 2ml tetrahydrofuran solution, adds tetrabutyl ammonium fluoride (1mmol), stirring at room 1 hour adds water 2ml washing back ethyl acetate extraction 3ml*3,
Anhydrous sodium sulfate drying, collection filtrate is spin-dried for and obtains white solid e 0.26g yield 94%.
Synthesizing of target compound paclitaxel lateral chain (f)
At N 2In the environment, compound (e) (0.7mmol) is dissolved in the 3ml dichloromethane solution, adds trifluoro vinegar 1.5ml acid, stirring at room 12 hours is spin-dried for solvent, adds the 1ml ethyl acetate, separates out solid.Filtration obtains product f0.15g, yield 78%.
Embodiment 2
Synthesizing of intermediate product (a)
At N 2Under the atmosphere, with 2,6 Dybenals (22mmol), (20mmol) acetic acid rhodium (0.1mmol) R-Binal phosphoric acid (0.4mmol) adds methylene dichloride 20ml down at 0 ℃ in the N-Ben Yajiaji-4 p-methoxy-phenyl imines, with peristaltic pump the diazoacetic acid tert-butyl ester (22mmol) is joined in the reaction system, time set is 1.5 hours.Added behind the diazoacetic acid tert-butyl ester stirring at room 0.5 hour, (ethyl acetate: normal hexane=1: 100～ethyl acetate: normal hexane=1: 20) separate and obtain product dr value 67:33ee value 88%, yield is 71% then to use column chromatography method.
Synthesizing of compound (b)
At N 2Under the atmosphere, (a) (5mmol) is dissolved in the 20ml methanol solution with intermediate product, adds 10%Pd/C (2.5g), ammonium formiate (20mmol), stirring at room 12 hours.Stop to stir, filter, use methanol wash Pd/C 3 times, add water 20ml washing after collection filtrate is spin-dried for, with ethyl acetate extraction (20ml*3), anhydrous sodium sulfate drying is spin-dried for and obtains white solid b 0.91g, and yield is 53%.In ethyl acetate: recrystallization obtains the product b0.76g of ee＞99% in normal hexane=10: 1 solution.
Synthesizing of compound (c)
At N 2In the environment, compound (b) (2mmol) is dissolved in 5ml N, in the N dimethyl formamide solution, stirs adding TERT-BUTYL DIMETHYL CHLORO SILANE (2.5mol) and imidazoles (5mmol) down, stirred 12 hours under 30 ℃ of temperature, add the 10ml water washing, use ethyl acetate extraction 10ml*5, collect extraction liquid, use anhydrous sodium sulfate drying, be spin-dried for white solid c 0.848g,, yield 93%.
Synthesizing of compound (d)
At N 2Under the atmosphere, compound (c) (1.8mmol) is dissolved in the 5ml acetonitrile solution, acetonitrile solution (the 2ml) (acetonitrile: water=5: 1) that under ice bath, adds ceric ammonium nitrate (6mmol), 0 ℃ of following stirring adds saturated aqueous solution of sodium bicarbonate adjusting PH after 10 hours be 8～9, with ethyl acetate extraction (20ml*4), collect extraction liquid, use anhydrous sodium sulfate drying, select the dried orange that obtains to be dissolved in the 5ml dichloromethane solution, at N 2Add triethylamine (4mmol) and Benzoyl chloride (2.4mmol) in the environment, stirring at room 4 hours, be spin-dried for solvent, (ethyl acetate: normal hexane=1: 40～ethyl acetate: normal hexane=1: 10), yield is 42% to obtain product d 0.27g with the column chromatography method separation.
Synthesizing of compound (e)
At N 2In the environment, compound (d) (0.8mmol) is dissolved in the 2ml tetrahydrofuran solution, adds tetrabutyl ammonium fluoride (1mmol), stirring at room 1 hour, add water 2ml washing back and use ethyl acetate extraction 3ml*3, anhydrous sodium sulfate drying, collection filtrate is spin-dried for and obtains white solid e 0.27g yield 97%.
Synthesizing of target compound paclitaxel lateral chain (f)
At N 2In the environment, compound (e) (0.7mmol) is dissolved in the 3ml dichloromethane solution, adds trifluoro vinegar 1.5ml acid, stirring at room 12 hours is spin-dried for solvent, adds the 1ml ethyl acetate, separates out solid.Filtration obtains product f0.14, yield 75%.
The structure of the foregoing description 1 and 2 intermediate product a is identified:
1H-NMR(CDCl 3，400MHz，δppm)7.01-7.21(8H，m)，6.54-6.56(2H，d)，6.37-6.39(2H，d)，4.87-4.89(1H，d)，4.61-4.64(2H，m)，3.99-4.00(1H，d)，3.57(3H，s)，1.31(9H，s)；
13C-NMR(CDCl 3，100MHz，δppm)169.30，151.94，141.30，139.48，136.92，132.18，130.04，128.20，128.13，127.20，127.12，114.85，114.52，82.22，81.97，66.77，60.49，55.55，27.90。

Claims (1)

1. the method for an asymmetric synthesis chiral paclitaxel lateral chain is characterized in that: chiral paclitaxel lateral chain (f) obtains by example reaction down:
Figure A2009100530480002C1
PMP=p-methoxyphenyl in the formula, TBSCl=TERT-BUTYL DIMETHYL CHLORO SILANE, TBS=tertiary butyl dimethyl, DMF=N, N dimethyl formamide, CAN=ceric ammonium nitrate, Et 3The N=triethylamine, TBAF=tetrabutyl ammonium fluoride, THF=tetrahydrofuran (THF);
The 1st step, intermediate product (a) synthetic: at N 2Protection down, with raw material 2,6 Dybenals (ii), N-benzylidene-4-anisidine (iii), the catalyst acetic acid rhodium and
Figure A2009100530480002C2
Acid adds in the reaction flask, under-20 ℃～30 ℃, with peristaltic pump the diazoacetic acid tert-butyl ester (i) is added wherein, the diazoacetic acid tert-butyl ester (i) being added the back in 1～2 hour stirred 0.5～1 hour under the room temperature, obtain intermediate product (a), then with column chromatography method with intermediate product (a) separation and purification; The molar ratio of above-mentioned reaction is diazonium tert.-butyl acetate (i): 2,6 Dybenals (ii): N-benzylidene-4-anisidine (iii): the acetic acid rhodium:
Figure A2009100530480002C3
Acid=1～2: 1～2: 1～1.5: 0.005～0.05: 0.01～0.1;
The 2nd step, compound (b) synthetic: at N 2Protection down, (a) is dissolved in the methanol solution with intermediate product, adds Pd/C and ammonium formiate, stirring at room 12～24 hours, stop to stir, filter, use methanol wash Pd/C 3～5 times, add water washing after collection filtrate is spin-dried for, with ethyl acetate extraction 3～5 times, anhydrous sodium sulfate drying is spin-dried for and obtains white solid compound (b), and above-mentioned reaction molar ratio is intermediate product (a): Pd/C: ammonium formiate=1: 0.5～2: 5～10;
The 3rd step, compound (c) synthetic: at N 2Protection down, (b) is dissolved in N with compound, in the N dimethyl formamide solution, stir adding TERT-BUTYL DIMETHYL CHLORO SILANE and imidazoles down, stirred 12～15 hours under 20 ℃～40 ℃ temperature, add water washing, with ethyl acetate extraction 3～5 times, collect extraction liquid, use anhydrous sodium sulfate drying, be spin-dried for white solid compound (c), above-mentioned reaction molar ratio is compound (b): TERT-BUTYL DIMETHYL CHLORO SILANE: imidazoles=1: 1.5～2.5: 2.5～5;
The 4th step, compound (d) synthetic: at N 2Protection down; (c) is dissolved in the acetonitrile solution with compound; the acetonitrile solution that under ice bath, adds ceric ammonium nitrate; acetonitrile solution is by acetonitrile: water=3～5: 1 part of mass ratio is formed, and 0 ℃ is stirred down and adds saturated aqueous solution of sodium bicarbonate after 8～10 hours to regulate PH be 8～9, with this solution of ethyl acetate extraction 3～5 times; collect extraction liquid; use anhydrous sodium sulfate drying, be spin-dried for the orange that obtains and be dissolved in the dichloromethane solution, at N 2Protection adds triethylamine and Benzoyl chloride down, and stirring at room 3～4 hours is spin-dried for solvent, separates obtaining white solid compound (d) with column chromatography method; The molar ratio of above-mentioned reaction is compound (c): ceric ammonium nitrate: triethylamine: Benzoyl chloride=1: 3～5: 2～3: 1.5～2;
The 5th step, compound (e) synthetic: at N 2Protection is dissolved in compound (d) in the tetrahydrofuran solution down, adds tetrabutyl ammonium fluoride, and stirring at room 1～2 hour adds after the water washing with ethyl acetate extraction 3～5 times, and anhydrous sodium sulfate drying is collected filtrate and is spin-dried for and obtains white solid compound (e); The molar ratio of above-mentioned reaction is compound (d): tetrabutyl ammonium fluoride=1: 1.2～1.5;
The 6th step, target compound paclitaxel lateral chain (f) synthetic: at N 2Protection is dissolved in substrate compounds (e) in the dichloromethane solution down, adds trifluoracetic acid, and stirring at room 12～15 hours is spin-dried for solvent, adds ethyl acetate, separates out solid target thing (f), filters and obtains white solid target compound (f); The molar ratio of above-mentioned reaction is compound (e): trifluoracetic acid=1: 5～10.
CNA2009100530488A 2009-06-15 2009-06-15 Method for asymmetric synthesis of chiral paclitaxel lateral chain Pending CN101585780A (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
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CN103044277A (en) * 2013-01-07 2013-04-17 华东师范大学 Preparation method of optical pure alpha-hydroxyl-beta-aminopropionic acid ester derivative
CN114195820A (en) * 2021-12-17 2022-03-18 中山大学 Isoserine derivative, preparation thereof and application thereof in synthesis of paclitaxel
CN114573631A (en) * 2022-03-10 2022-06-03 清远中大创新药物研究中心 Method for synthesizing paclitaxel side chain and analog thereof in one step by utilizing three-component reaction and application thereof
CN114621986A (en) * 2020-12-10 2022-06-14 湖南引航生物科技有限公司 Method for biosynthesis of paclitaxel side chain
CN114621985A (en) * 2020-12-10 2022-06-14 湖南引航生物科技有限公司 Method for synthesizing paclitaxel side chain by biological catalysis

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103044277A (en) * 2013-01-07 2013-04-17 华东师范大学 Preparation method of optical pure alpha-hydroxyl-beta-aminopropionic acid ester derivative
CN103044277B (en) * 2013-01-07 2015-04-08 华东师范大学 Preparation method of optical pure alpha-hydroxyl-beta-aminopropionic acid ester derivative
CN114621986A (en) * 2020-12-10 2022-06-14 湖南引航生物科技有限公司 Method for biosynthesis of paclitaxel side chain
CN114621985A (en) * 2020-12-10 2022-06-14 湖南引航生物科技有限公司 Method for synthesizing paclitaxel side chain by biological catalysis
CN114621986B (en) * 2020-12-10 2024-04-12 湖南引航生物科技有限公司 Method for biosynthesis of taxol side chain
CN114621985B (en) * 2020-12-10 2024-04-16 湖南引航生物科技有限公司 Method for synthesizing taxol side chain by biocatalysis
CN114195820A (en) * 2021-12-17 2022-03-18 中山大学 Isoserine derivative, preparation thereof and application thereof in synthesis of paclitaxel
CN114195820B (en) * 2021-12-17 2023-11-10 中山大学 Isoserine derivative, preparation thereof and application thereof in taxol synthesis
CN114573631A (en) * 2022-03-10 2022-06-03 清远中大创新药物研究中心 Method for synthesizing paclitaxel side chain and analog thereof in one step by utilizing three-component reaction and application thereof
CN114573631B (en) * 2022-03-10 2024-06-18 清远中大创新药物研究中心 Method for synthesizing taxol side chain and analogues thereof by three-component reaction in one step and application thereof

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