CN101081841A - Novel 2'-alpha-hydroxyalkyl taxone compound and preparation method thereof - Google Patents

Novel 2'-alpha-hydroxyalkyl taxone compound and preparation method thereof Download PDF

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Publication number
CN101081841A
CN101081841A CNA2006100270237A CN200610027023A CN101081841A CN 101081841 A CN101081841 A CN 101081841A CN A2006100270237 A CNA2006100270237 A CN A2006100270237A CN 200610027023 A CN200610027023 A CN 200610027023A CN 101081841 A CN101081841 A CN 101081841A
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compound
representative
cycloalkyl
alkyl
group
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南发俊
周净
李佳
谢传明
张仰明
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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Priority to PCT/CN2007/001733 priority patent/WO2007137513A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The present invention provides one kind and has the following structure 2 '-alpha-hydroxyalkyl bearing taxanes of formula and pharmaceutical composition and its application including the compound. Such compound can effectively inhibit the growth of tumour cell, especially for the growth (such as MCF-7/ADR) of multidrug resistance tumor cells, compared with taxol (Paclitaxel, Taxol
Figure 200610027023.7_AB_0
) and Docetaxel (Docetaxel, Taxotere
Figure 200610027023.7_AB_0
) effect is remarkably reinforced.

Description

2 '-alpha-hydroxyalkyl bearing taxanes of one class novelty and preparation method thereof
Technical field
The present invention relates to the semisynthetic taxol compound of a class, more specifically relate to a class 2 '-alpha-hydroxyalkyl bearing taxanes.
Background technology
Cancer is with cellular abnormality propagation and to shift be a big class disease of characteristics, has become one of disease of serious harm human health, according to World Health Organization's statistics, and the annual cases of cancer 600 ten thousand that increases newly in the whole world.In China, cancer has become the second largest deadly cause of disease that is only second to cardiovascular and cerebrovascular diseases.
Taxol (Paclitaxel, trade(brand)name Taxol) is a kind of diterpene-kind compound with antitumour activity by separation and Extraction in the Chinese yew genus plants bark.Taxol promotes that tubulin polymerization forms stable microtubule, and suppresses the depolymerization of microtubule by combining with the cell tubulin, finally cause forming the afunction of microtubule fasolculus, thereby the mitotic division of blocking-up cell reaches anticancer effect.Recent studies show that, taxol also has powerful promotion cancerous tumor cell and transfers the ability of dying except the mitotic division that can suppress cancerous tumor cell.Docetaxel (Docetaxel, trade(brand)name Taxotere) is taxol to be carried out in structural modification and the transformation process by the synthetic gained of semisynthesis.Docetaxel antitumous effect mechanism is identical with taxol, but with respect to taxol, it has better bioavailability, and toxic side effect is less, antitumour activity is better than taxol, simultaneously because its water-soluble increase, makes the easier preparation of making of Docetaxel.
Figure A20061002702300101
Taxol: R 1=CH 3CO; R 2=C 6H 5
Docetaxel: R 1=H; R 2=(CH 3) 3CO
Since in December, 1992, the drugs approved by FDA taxol was used for the treatment of advanced ovarian cancer, the range of application of taxol was expanded gradually, had become widely used clinically first-selected cancer therapy drug.It is when bringing hope to the cancer patients, and also for drugmaker has brought huge economic benefit, 2000, the sales volume of formulation for paclitaxel reached 15.92 hundred million dollars.
Because taxol is detected in the Ramulus et folium taxi cuspidatae plant bark, this seeds quantity rareness, poor growth, 1 kilogram of taxol of actual production needs about 30 tons of bark of Ramulus et folium taxi cuspidatae, and simple extraction separation can not satisfy market demand far away.1988; people such as Denis at first utilize 10-deacetylate baccatin III (10-DAB) to obtain taxol (J.-N.Denis by semisynthetic method; A.E.Greene; D.Guenard, L.M.Gueritte-Voegelein, P.Potier; J.Am.Chem.Soc.; 1988,110,5917-5919).1993, Holton used beta-lactam and 10-DAB link coupled method first, the efficient semi-synthetic taxol (US-05254703,1993) that obtains.
Figure A20061002702300102
10-deacetylate baccatin III (10-DAB)
Since the 1980s, people are being devoted to the structure and the activity relationship research of taxol always, wish by these researchs taxol to be carried out structural modification and transformation, in the hope of finding the paclitaxel kind anti-cancer drugs thing of new generation of high-efficiency low-toxicity.
Structure of modification at 2 ' of taxol benzene isoserine side chain is less relatively, synthetic 2 '-methyl Docetaxel (J.-N.Denis, A.Fkyerat, the Y.Gimbert of obtaining of people such as Denis, C.Coutterez, P.Mantellier, S.Jost and A.E.Greene, J.Chem.Soc., PerkinTrans.1,1995,1811), active testing shows that its cytotoxicity (KB-VI) and microtubule depolymerization activity all are better than Docetaxel.This may be the introducing because of 2 '-methyl, has reduced the rotary freedom of C-2 '-C-3 '.
Figure A20061002702300111
2 '-the methyl Docetaxel
The present inventor synthesizes the 2 '-alpha-hydroxyalkyl bearing taxanes that obtains a class novelty by with 10-DAB and the beta-lactam coupling that is fit to replace.
Summary of the invention
An object of the present invention is to carry out structure of modification at 2 ' of the benzene isoserine side chain of taxol and Docetaxel, design and synthesize 2 '-alpha-hydroxyalkyl bearing taxanes of a class novelty, and its structure and activity relationship are carried out deep research.
Another object of the present invention provides the method for this 2 '-alpha-hydroxyalkyl bearing taxanes of preparation.
A further object of the present invention provides the application of this compound in the pharmaceutical composition of treatment cancer.
Compound of the present invention has the structure shown in the following general formula 1:
General formula 1
Figure A20061002702300121
Wherein:
R 1Representative-C (O) C 6H 5,-C (O) OC (CH 3) 3
R 2Representative-H; The C1-C6 alkyl; The C3-C6 cycloalkyl; The C1-C6 alkyl that methoxyl group, oxyethyl group or hydroxyl replace; The C3-C6 cycloalkyl that methoxyl group, oxyethyl group or hydroxyl replace; Phenyl; Or benzyl;
R 3Representative-H or-C (O) CH 3
R 4Representative-H ,-OH or-F;
And comprise 2 ', 3 ', and all possible steric isomer in 2 ' α position.
Wherein work as R 1For-C (O) C 6H 5The time, R 3For-C (O) CH 3
R 2For-H; The C1-C6 alkyl; The C3-C6 cycloalkyl; The C1-C6 alkyl that methoxyl group, oxyethyl group or hydroxyl replace; The C3-C6 cycloalkyl that methoxyl group, oxyethyl group or hydroxyl replace; Phenyl; Or benzyl;
R 4For-H ,-OH or-F, this compound is the compound with following structural formula:
Figure A20061002702300131
Wherein, work as R 1For-C (O) OC (CH 3) 3The time, R 3For-H;
R 2For-H; The C1-C6 alkyl; The C3-C6 cycloalkyl; The C1-C6 alkyl that methoxyl group, oxyethyl group or hydroxyl replace; The C3-C6 cycloalkyl that methoxyl group, oxyethyl group or hydroxyl replace; Phenyl; Or benzyl;
R 4For-H ,-OH or-F, this compound is the compound with following structural formula:
Figure A20061002702300132
Compound of the present invention is selected from the group that comprises following compound:
Compound 1a
Compound 1b
Figure A20061002702300141
Compound 1c
Compound 1d
Figure A20061002702300143
Compound 1e
Figure A20061002702300144
Compound 1f
Figure A20061002702300151
Compound 1g
Figure A20061002702300152
Compound 1h
Compound 1i
Figure A20061002702300154
With
Compound 1j
The present invention also provides the method for preparation 2 '-alpha-hydroxyalkyl bearing taxanes, and this method may further comprise the steps:
Compound 2 and compound 3 carry out removing protecting group and obtaining final compound 1 after esterification obtains coupled product.
Wherein, esterification is a solvent with THF, toluene or pyridine, uses condensing agents such as DCC, n-BuLi, two trimethyl silicane ammonia lithium or two trimethyl silicane ammonia sodium, can add DMAP as catalyzer according to reaction needed, and temperature of reaction is at-50 ℃～90 ℃.
Can select different protecting group removal methods for use according to the difference of protecting group.
The time of general reaction decides as the case may be, usually come the performance level of tracking and measuring reaction with TLC, after finishing, reaction generally extracts with ethyl acetate or methylene dichloride equal solvent, use 5%HCl, water, saturated common salt washing successively, after drying, low-temperature reduced-pressure removes and desolvates, and enriched material is through column chromatographic isolation and purification, and methods such as final product use nuclear-magnetism prove.
Concrete preparation process can be represented by following reacting flow chart:
Figure A20061002702300171
Wherein:
R 1Representative-C (O) C 6H 5,-C (O) OC (CH 3) 3
R 2Representative-H; The C1-C6 alkyl; The C3-C6 cycloalkyl; The C1-C6 alkyl that methoxyl group, oxyethyl group or hydroxyl replace; The C3-C6 cycloalkyl that methoxyl group, oxyethyl group or hydroxyl replace; Phenyl; Or benzyl;
R 3Representative-H or-C (O) CH 3
R 4Representative-H ,-OH or-F;
And comprise all possible steric isomer in 2 ', 3 ' and 2 ' α position.
Wherein:
R 5Represent hydroxy-protective groups such as TMS, TES, TBDMS, EE;
R 6Representative-C (O) CH 3, hydroxy-protective group such as TMS, TES, Troc;
R 7Represent hydroxy-protective groups such as TMS, TES, Troc.
Wherein compound 2 has adopted two kinds of different synthetic methods according to the difference of its cis-trans isomerism:
(1) synthetic route of trans-compound 2 is as follows:
Figure A20061002702300181
Wherein:
R 1Representative-C (O) C 6H 5,-C (O) OC (CH 3) 3
R 2Representative-H; The C1-C6 alkyl; The C3-C6 cycloalkyl; The C1-C6 alkyl that methoxyl group, oxyethyl group or hydroxyl replace; The C3-C6 cycloalkyl that methoxyl group, oxyethyl group or hydroxyl replace; Phenyl; Or benzyl;
R 4Representative-H ,-OH or-F;
R 5Represent hydroxy-protective groups such as TMS, TES, TBDMS or EE.
Compound 4 is at THF/H 2In the mixed solvent of O with PhSO 2The Na reaction obtains compound 5; Use THF as solvent, compound 5 obtains compound 6 with Grignard reagent PhMgBr reaction; CH 2Cl 2As solvent, compound 6 with PhC (O) Cl or (Boc) 2O obtains compound 3,4-anti-2 under TEA and little amount of catalyst DMAP effect.
Wherein, compound 4 can be synthetic according to the method for patent EP 0369691.
(2) synthetic route of cis-compound 2 is as follows: (reference literature J.Am.Chem.Soc.1998,120, the method for 5840-5841)
Wherein:
R 1Representative-C (O) C 6H 5,-C (O) OC (CH 3) 3
R 2Representative-H; The C1-C6 alkyl; The C3-C6 cycloalkyl; The C1-C6 alkyl that methoxyl group, oxyethyl group or hydroxyl replace; The C3-C6 cycloalkyl that methoxyl group, oxyethyl group or hydroxyl replace; Phenyl; Or benzyl;
R 4Representative-H ,-OH or-F;
R 5Represent hydroxy-protective groups such as TMS, TES, TBDMS or EE.
More than Fan Ying temperature of reaction is generally 0 ℃ to room temperature or Heating temperature to 80 ℃～120 ℃.Reaction times decides according to concrete reactant, comes the performance level of tracking and measuring reaction usually with TLC.The general post-treating method that adopts comprised that cooling, concentration of reaction solution eliminate solvent, extraction, column chromatography for separation etc. after reaction finished.Final product detects proof with NMR.
This compound can be used for preparing the medicine for the treatment of cancer.
Below, by embodiment and comparative example the present invention will be described more specifically.Yet the following examples only are to provide for explanation, so the present invention is not limited to these embodiment or is limited by them.
Embodiment
Among the following embodiment, conventional post-treating method is: after reaction is finished, add an amount of water in reaction solution, separate organic phase and water, water merges organic phase after fully extracting through organic solvents such as ethyl acetate, ether or methylene dichloride.If needed, use 5%HCl solution and/or saturated NaHCO successively 3Solution, water and saturated common salt water washing.Organic phase is used anhydrous Na again 2SO 4Perhaps anhydrous MgSO 4Drying, decompression is spin-dried for after filtering, and obtains crude product, again through obtaining final product after the column chromatographic isolation and purification.
The Mercury-Vx 300M Instrument measuring that MR produces with Varian, NMR calibration: δ H 7.26ppm (CDCl3).Reagent is mainly provided by Shanghai chemical reagents corporation, and purifying products is mainly used column chromatography, silica gel (200-300 order), and the used silica gel model of column chromatography is gross porosity (ZLX-II), is produced by subsidiary factory of Haiyang Chemical Plant, Qingdao.
Embodiment 1: the preparation of compound 5a
Prepare compound 5a according to following reaction formula.
The 10ml THF solution that in the 50ml round-bottomed flask, adds 718mg compound 4a (2.5mmol), and the 10ml aqueous solution of 1000mg benzene sulfinic acid sodium salt (5mmol).Reaction solution refluxed 1 hour for 80 ℃, and reaction finishes postcooling to room temperature, obtains 840mg compound 5a through conventional aftertreatment.
Figure A20061002702300211
Except using the corresponding compounds raw material, prepare compound (±) 5a, 5b, (±) 5b with above-mentioned identical method, wherein (±) 5a, (±) 5b are respectively the racemoid that comprises 5a, 5b and their enantiomer.Its structural formula and nuclear magnetic data are as shown in table 1 below.
Table 1
Embodiment 2: the preparation of compound 6a
Prepare compound 6a according to following reaction formula.
840mg compound 5a (2.28mmol) is dissolved in the 10ml THF solution, and-20 ℃ were stirred 15 minutes, dripped the THF solution of 4.6ml 1M PhMgBr.After dropwising,, continue reaction 1 hour at 0 ℃ again-20 ℃ of reactions 2 hours.After reacting completely, add saturated ammonium chloride solution cancellation reaction, obtain 472mg compound 6a through conventional aftertreatment.
Figure A20061002702300221
Except using the corresponding compounds raw material, prepare compound (±) 6a with above-mentioned identical method, 6b, (±) 6b, wherein (±) 6a, (±) 6b are respectively the racemoid that comprises 6a, 6b and their enantiomer.Its structural formula and nuclear magnetic data are as shown in table 2 below.
Table 2
Figure A20061002702300231
Embodiment 3: the preparation of compound 2a
Prepare compound 2a according to following reaction formula.
In the 10ml dichloromethane solution, add 472mg compound 6a (1.55mmol), 0.5ml triethylamine (2.3mmol), 405mg (Boc) 2The DMAP of O (1.86mmol) and catalytic amount.Reaction solution stirring at room 6 hours after reaction finishes, obtains 564mg compound 2a through conventional aftertreatment.
Figure A20061002702300232
Except using the corresponding compounds raw material, prepare compound (±) 2a, 2b with above-mentioned identical method, (±) 2b, 2c, (±) 2c, wherein (±) 2a, (±) 2b, (±) 2c are respectively the racemoid that comprises 2a, 2b, 2c and their enantiomer.Its structural formula and nuclear magnetic data are as shown in table 3 below.
Table 3
Figure A20061002702300241
Embodiment 4: the preparation of compound 2d
Prepare compound 2d according to following reaction formula.
The DMAP that in the 10ml dichloromethane solution, adds 472mg compound 6a (1.55mmol), 0.5ml triethylamine (2.3mmol), 0.25ml Benzoyl chloride (1.86mmol) and catalytic amount.Reaction solution stirring at room 6 hours after reaction finishes, obtains 564mg compound 2d through conventional aftertreatment.
Figure A20061002702300251
Except using the corresponding compounds raw material, prepare compound (±) 2d, 2e with above-mentioned identical method, (±) 2e, 2f, (±) 2f, wherein (±) 2d, (±) 2e, (±) 2f are respectively the racemoid that comprises 2d, 2e, 2f and their enantiomer.Its structural formula and nuclear magnetic data are as shown in table 4 below.
Table 4
Figure A20061002702300252
Figure A20061002702300261
Embodiment 5: the preparation of compound 1a
Prepare compound 2d according to following reaction formula.
178mg compound 7,10-Di-Troc-DAB (0.2mmol) is dissolved in the 1ml THF solution,-40 ℃ of hexane solutions that drip 0.22ml 2.5M n-BuLi, reaction solution stirred 30 minutes under this temperature, added the 1ml THF solution of 162mg compound 2a (0.4mmol) again.React and be warming up to 0 ℃ naturally after 30 minutes, continuation reaction 1 hour.Saturated ammonium chloride solution cancellation reaction, conventional aftertreatment obtains the 145mg coupled product.
Ice-water bath, the 145mg coupled product is dissolved in the 2ml THF solution, the THF solution that adds the tetrabutyl ammonium fluoride of 0.22ml 1M, reaction rises to room temperature, TLC following response process adds 2ml acetic acid and 0.25ml water, vigorous stirring 30 minutes after reaction finishes, add zinc powder again, conventional aftertreatment obtained compound 1a 58mg after reaction finished.
Figure A20061002702300271
Except using the corresponding compounds raw material, prepare compound 1b, 1c, 1d, 1e with above-mentioned identical method, its structural formula and nuclear magnetic data are as shown in table 5 below.
Table 5
Figure A20061002702300272
Figure A20061002702300281
Embodiment 6: the preparation of compound 1f
Prepare compound 2d according to following reaction formula.
140mg compound 7-TES-Baccatin III (0.2mmol) is dissolved in the 1ml THF solution,-40 ℃ of hexane solutions that drip 0.22ml 2.5M n-BuLi, reaction solution stirred 30 minutes under this temperature, added the 1ml THF solution of 164mg compound 2d (0.4mmol) again.React and be warming up to 0 ℃ naturally after 30 minutes, continuation reaction 1 hour.Saturated ammonium chloride solution cancellation reaction, conventional aftertreatment obtains the 122mg coupled product.
Ice-water bath, 122mg coupled product are dissolved in the 2ml THF solution, add the THF solution of the tetrabutyl ammonium fluoride of 0.22ml 1M, and reaction rises to room temperature, and TLC following response process obtains 62mg compound 1f through conventional aftertreatment after reaction finishes.
Figure A20061002702300291
Except using the corresponding compounds raw material, prepare compound 1g, 1h, 1i, 1j with above-mentioned identical method, its structural formula and nuclear magnetic data are as shown in table 6 below.
Table 6
Figure A20061002702300301
Embodiment 7: the active testing test
The test philosophy of medicaments sifting model:
The MTT analytical method with metabolism reduce 3-(4,5-dimethylthylthiazol-2-y1)-2,5-diphenyl tetrazolium bromide (MTT) be the basis.Have the desaturase relevant with NADP in the plastosome of viable cell, xanchromatic MTT can be reduced to insoluble hepatic Formazan, this enzyme of dead cell disappears, and MTT is not reduced.With available microplate reader behind the DMSO dissolving Formazan in 550/690nm wavelength place measuring light density.
Mtt assay is surveyed the cell proliferation experiment operation steps:
Take the logarithm vegetative period, cell growth state good attached cell MCF-7 and MCF-7/ADR through 0.05% trysinization, counting is made into cell suspension with substratum, the counting back by every hole 3000 cell 100ul culture medium inoculated in 96 orifice plates; 96 good in connecing orifice plates are moved into 37 ℃, 5%CO 2Incubator in spend the night and treat cell attachment; Beginning dosing in second day, dosing fore portion control wells directly adds MTT solution (5mg/ml) 20ul (need not inhale substratum) effect and read A550/690 as initial cell concentration afterwards in 3 hours, every hole, medicine hole adds the substratum that 100ul contains the 2ul compound, with DMSO is the background contrast, equally also be the DMSO of the interior 2ul of adding of substratum of every hole 100ul, and each experiment all have the positive control Zorubicin.Place 37 ℃, 5%CO 2Incubator in 72 hours, each compound is done three multiple holes (draw the 6ul compound in the eppendorf of the bacterium of going out pipe, add 300ul substratum mixing then add respectively in three holes), each compound is done six concentration gradients; (72 hours) every hole directly adds MTT solution (5mg/ml) 40ul (need not inhale substratum) after three days, puts into incubator and takes out after three hours hole liquid is blotted, and adds 100ulDMSO again, and slight vibration is fully dissolved crystallisate; (550/690) detects the absorbance value in each hole as the cell density after the drug effect on enzyme connection detector.Medicine reflects with the clean growth rate of percentage the proliferation inhibition rate of tumour cell MCF-7 and MCF-7/ADR, grows only-compound concentration functional arrangement mensuration IC50 value from percentage.The calculation formula of the clean growth rate of percentage
The clean growth rate of percentage=[the initial A550/690 of (cell+medicine) A550/690-]/[the initial A550/690 of (cell+pharmaceutical carrier) A550/690-]
Table 7: sample test result
Numbering IC 50(MCF-7) IC 50(MCF-7/ADR) Numbering IC 50(MCF-7) IC 50(MCF-7/ADR)
Docetaxel (Taxotere) 2.06nM 0.98μM Taxol (Taxol) 5.02nM 4.65μM
Compound 1a 16.79μM 94.42μM Compound 1f 3.22μM 6.34μM
Compound 1b ＞20μM ＞1mM Compound 1g ＞20μM 15.85μM
Compound 1c 18.09μM ＞1mM Compound 1h 4.96μM 12.14μM
Compound 1d ＞20μM ＞1mM Compound 1i ＞20μM 50.88μM
Compound 1e ＞20μM ＞1mM Compound 1j ＞20μM 24.71μM
According to the test-results of last table as can be seen, the compound of the present invention effect that has stronger anticancer growth with respect to the Docetaxel (Taxotere) and the taxol (Taxol) of prior art.

Claims (8)

1, a class has 2 '-alpha-hydroxyalkyl bearing taxanes and 2 ', 3 ' of following general formula 1 structure, and all possible steric isomer in 2 ' α position:
General formula 1
Wherein:
R 1Representative-C (O) C 6H 5Or-C (O) OC (CH 3) 3
R 2Representative-H; The C1-C6 alkyl; The C3-C6 cycloalkyl; The C1-C6 alkyl that methoxyl group, oxyethyl group or hydroxyl replace; The C3-C6 cycloalkyl that methoxyl group, oxyethyl group or hydroxyl replace; Phenyl; Or benzyl;
R 3Representative-H or-C (O) CH 3
R 4Representative-H ,-OH or-F.
2, compound according to claim 1 is characterized in that: this compound is the compound with following structural formula:
Wherein, work as R 1For-C (O) C 6H 5The time,
R 3For-C (O) CH 3
R 2For-H; The C1-C6 alkyl; The C3-C6 cycloalkyl; The C1-C6 alkyl that methoxyl group, oxyethyl group or hydroxyl replace; The C3-C6 cycloalkyl that methoxyl group, oxyethyl group or hydroxyl replace; Phenyl; Or benzyl;
R 4For-H ,-OH or-F.
3, compound according to claim 1 is characterized in that: this compound is the compound with following structural formula:
Wherein, work as R 1For-C (O) OC (CH 3) 3The time,
R 3For-H;
R 2For-H; The C1-C6 alkyl; The C3-C6 cycloalkyl; The C1-C6 alkyl that methoxyl group, oxyethyl group or hydroxyl replace; The C3-C6 cycloalkyl that methoxyl group, oxyethyl group or hydroxyl replace; Phenyl; Or benzyl;
R 4For-H ,-OH or-F.
4, compound according to claim 1 is characterized in that: this compound is selected from the group that comprises following compound:
Compound 1a
Compound 1b
Figure A2006100270230004C2
Compound 1c
Figure A2006100270230004C3
Compound 1d
Compound 1e
Compound 1f
Figure A2006100270230005C2
Compound 1g
Compound 1h
Figure A2006100270230005C4
Compound 1i
Figure A2006100270230006C1
With
Compound 1j
Figure A2006100270230006C2
5, a kind of method for preparing the described compound of claim 1 may further comprise the steps:
Compound 2 and 10-deacetylate baccatin III carry out removing protecting group and obtaining final compound after esterification obtains coupled product,
Figure A2006100270230006C3
10-deacetylate baccatin III compound 2
Wherein:
R 1Representative-C (O) C 6H 5Or-C (O) OC (CH 3) 3
R 2Representative-H; The C1-C6 alkyl; The C3-C6 cycloalkyl; The C1-C6 alkyl that methoxyl group, oxyethyl group or hydroxyl replace; The C3-C6 cycloalkyl that methoxyl group, oxyethyl group or hydroxyl replace; Phenyl; Or benzyl;
R 4Representative-H ,-OH or-F;
R 5Representative-H, TMS, TES, TBDMS or EE hydroxy-protective group.
According to the preparation method of claim 2, it is characterized in that 6, trans-compound 2 prepares by following reacting flow chart:
Figure A2006100270230007C1
Wherein:
R 1Representative-C (O) C 6H 5,-C (O) OC (CH 3) 3
R 2Representative-H; The C1-C6 alkyl; The C3-C6 cycloalkyl; The C1-C6 alkyl that methoxyl group, oxyethyl group or hydroxyl replace; The C3-C6 cycloalkyl that methoxyl group, oxyethyl group or hydroxyl replace; Phenyl; Or benzyl;
R 4Representative-H ,-OH or-F;
R 5Represent TMS, TES, TBDMS or EE hydroxy-protective group;
Compound 4 is at THF/H 2In the mixed solvent of O with PhSO 2The Na reaction obtains compound 5; Use THF as solvent, compound 5 obtains compound 6 with Grignard reagent PhMgBr reaction; CH 2Cl 2As solvent, compound 6 with PhC (O) Cl or (Boc) 2O obtains compound 3,4-anti-2 under TEA and little amount of catalyst DMAP effect.
7, a kind of pharmaceutical composition that is used for the treatment of cancer is characterized in that, comprises the compound and the pharmaceutically acceptable carrier of claim 1.
According to the described pharmaceutical composition of claim 4, it is characterized in that 8, wherein said cancer is the multidrug resistance tumour.
CNA2006100270237A 2006-05-29 2006-05-29 Novel 2'-alpha-hydroxyalkyl taxone compound and preparation method thereof Pending CN101081841A (en)

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CN101838251A (en) * 2010-06-01 2010-09-22 翟雄 Method for semi-synthesizing paclitaxel and docetaxel
CN104689330A (en) * 2013-12-06 2015-06-10 上海交通大学 Antitumor drug PEGylation and applications of antitumor drug PEGylation in reversal of tumor multidrug resistance

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