CN101648973A

CN101648973A - Water-soluble taxane and preparation method thereof

Info

Publication number: CN101648973A
Application number: CN200910102205A
Authority: CN
Inventors: 漆又毛; 揭清; 张冯敏; 顾颖
Original assignee: Individual
Current assignee: Hangzhou Adamerck Pharmlabs Inc
Priority date: 2009-09-03
Filing date: 2009-09-03
Publication date: 2010-02-17
Anticipated expiration: 2029-09-03
Also published as: CN101648973B

Abstract

The invention provides water-soluble taxane which comprises water-soluble four-ring taxane, water-soluble five-ring taxane and water-soluble six-ring taxane. Taxane (a) reacts with the formula (1) under the existence of alkali to obtain ester (b) of which the second site or the seventh site or the second site and the seventh site are substituted; and the (b) reacts with the formula (2) to obtain atarget product. The water-soluble taxane has favorable water solubility and can be directly made into powder injection or transfusion without adding a surface active agent and an oily auxiliary material during preparation, can be also made into oral preparation because of favorable bioavailability, and can be used for preparing a treating medicine for clinically treating tumor patients. On one hand, the water-soluble taxane is convenient for clinical application, on the other hand, the compliance of the patients is improved, thereby having obvious advantages and market value. The structural formula is shown as the formula (3).

Description

Water-soluble taxane and preparation method

Technical field

The invention belongs to medical technical field, relate to water-soluble taxane structure, preparation method and application, solved the problem and the oral difficult absorption problem of the water-soluble fluidity difference of Taxan.

Background technology

Taxol (paclitaxel, trade(brand)name Taxol) is the diterpene-kind compound by a kind of unique antitumour activity of Chinese yew genus plants bark or needle separation and Extraction, and its chemical structure is novel complicated, the mechanism of action uniqueness, and antitumour activity is stronger.The taxol chemical structure is:

Taxol acts on microtubule/tubulin system, and it can promote that tubulin is assembled into microtubule, suppresses the depolymerization of microtubule, thereby it is unusual to cause microtubule fasolculus to be arranged, and forms aster, makes spindle body lose normal function, causes cancer cell death.Taxol is acknowledged as the tumor chemotherapeutic drug of new generation with important breakthrough with its unique anticancer mechanism.As broad-spectrum anti-cancer drug, taxol has better curative effect to ovarian cancer, mammary cancer, lung cancer, the esophageal carcinoma, melanoma, incidence cancer.Taxol is now got permission clinical application in more than 60 countries, is considered to one of best cancer therapy drug of the human so far curative effect of finding.

The solubleness of taxol in water has only 0.25 μ g/ml, water-soluble hardly, utilization ratio is low in vivo, so the taxol in the paclitaxel injection of existing clinical use is (to stablize with 1: 1 mixed solution with dewatered ethanol and dissolve by polyoxyethylenated castor oil, concentration is 6mgmL-1, is diluted to final administration volume with physiological saline or 5% glucose before using.Polyoxyethylenated castor oil has the effect that promotes histamine release, often causes severe anaphylactic reaction, so patient need resist quick processing in advance before administration; Lack tumor-targeting simultaneously, high dosage easily produces untoward reaction.

Obtaining the taxol albumin microparticle lyophilized powder of drugs approved by FDA and liposomal encapsulated taxol injection recently goes on the market.Albumin and liposome be as the taxol movement system, though can change its intravital pharmacokinetics behavior, level of application is subjected to the restriction of its encapsulation rate and stability, the problem of and poor stability low as the taxol encapsulation rate of albumin microparticle; The taxol of liposome is rapid seepage or the seepage before the no show target tissue from liposome, is the defective of being badly in need of change.

At present domestic still have injection taxol, injection taxol (phospholipid complex), injection taxol (nanoparticle), injection taxol albumin microparticle, taxol (precursor) lipidosome injection, injection taxol polymer micelle, paclitaxel lipid microspheres injection in batch clinical formulation.

Disclosed data shows that introducing ammonium salt, carboxylate salt, sulfonate, ammonia amino acid salts, phosphoric acid salt, polyoxyethylene glycol-groups such as 2000-diacid-proline(Pro) in Taxan makes the water-soluble paclitaxel prodrug, as:

Application number is 91105549.5 patent disclosure through sulfonated 2 '-the acryloyl taxol and through sulfonated 2 '-O-acyl acid taxol derivative, they have the water-soluble and stable of improvement, possess biological activity simultaneously.

CN1217662 discloses the water-soluble composition of taxol and Japanese yew ester, and it makes the polymkeric substance conjugation of taxol or dcetaxel and water-soluble chelator, polyoxyethylene glycol or poly-(1-L-glutamic acid) or poly-(1-aspartic acid) and so on.

CN1283619 relates to a kind of water-soluble polyhydroxyl derivative of taxol and makes each method.Use isobutyl chlorocarbonate as activating reagent, form mixed acid anhydride with 2 '-O-acyl acid taxol, as oxygen affinity nuclear reagent attack glycerol, high reactivity, highly selective generate monoesters.

CN1288890 relates to the water soluble taxad alcohol derivative that a class contains thiosulfuric acid or its salt, and this derivative can be used for tumour and treatment for cancer.With existing medicinal single taxol relatively, have and keep former effective in cure, reduce toxic side effect, the advantage that bioavailability is high.

CN101028259 discloses the water-soluble composition of taxol and Japanese yew ester, and it makes the polymkeric substance conjugation of taxol or dcetaxel and water-soluble chelator, polyoxyethylene glycol or poly-(1-L-glutamic acid) or poly-(1-aspartic acid) and so on.Also disclose the taxol of taking in this combination treatment tumour, rheumatoid arthritis and so on autoimmune disease and prediction tumour, and be used for radiolabeled diethylene triaminepentaacetic acid(DTPA) (DTPA) taxol tumor imaging.Other embodiment comprises that the coating implantable stents is with prevention of restenosis.

CN101062925 discloses a class side chain and has contained secondary amine groups, the new D51-7059 of good water solubility.

CN101274924 the present invention relates to a kind of suitable industrial application " one kettle way ", is used to prepare taxol and derivative thereof.It is raw material that this method is removed acetyl-bearing taxanes with the 10-that contains hydroxyl on C (2 ') and C (10) position simultaneously; under the katalysis of metallic element salt; use the hydroxyl on diacetyl oxide highly selective acylation C (2 ') position and C (10) position; in reaction system, add superoxide and alkaline matter subsequently; ethanoyl on selective hydrolysis C (2 ') position, thus the bearing taxanes of C (10) position glycoloylization obtained.

Up to the present, mostly be in the Taxan and introduce modification group in 2 ' or 7 s' the alcohol radical and conduct a research.People are also in the water-soluble and absorption problem of making great efforts to solve taxol.

Summary of the invention

The purpose of this invention is to provide a kind of water-soluble taxane, have general structure (I):

Wherein:

A is the Japanese yew alkanol residue that has 2 ', 7 hydroxyl, and described Japanese yew alkanol residue is in Fourth Ring Japanese yew alkanol residue, pentacycle taxane alcohol residue, the six ring Japanese yew alkanol residues;

N is in 0 or 1, and when n is 0, only there is hydroxyl in described Taxan at 2 '; When n is 1, all there is hydroxyl in described Taxan at 2 ', 7;

B and B ' be H or In one, except that B and B ' can not be the H simultaneously, B and B ' can be identical, also can be different, in the formula:

R is H, contain the fat alkane of 2 to 7 carbon,

In one, R wherein ₀Be one in H, F, Cl, Br, oxy radical, the nitrogen-containing group; X and X ' are among O, the S; M or M ' be H, Na, K, Cs, Li, NH4, Ca, Mg, CH3, CF3, C2H5, C3H7, C4H9, C6H5, CH2C6H5, in one.

Compound of the present invention (I), when A be Fourth Ring Japanese yew alkanol residue, when n is 1, its water-soluble Fourth Ring Taxan has the structure of general formula (II):

Wherein:

R ₁Be C ₆H ₅-or (CH ₃) ₃Among the CO-one;

R ₂Be H or CH ₃Among the CO-one;

The same compound of B and B ' (I) is described.

Compound of the present invention (I) when A be pentacycle taxane alcohol residue, when n is 1, its water-soluble pentacycle taxane has the structure of general formula (III):

Wherein:

R ₃Be

In one;

R ₄Be

In one;

The same compound of B and B ' (I) is described.

Compound of the present invention (I) when A be pentacycle taxane alcohol residue, when n is 0, its water-soluble pentacycle taxane has the structure of general formula (IV):

Wherein:

R ₅Be halogen atom or alkoxyl group with 1 to 6 carbon atom;

R ₆Be in hydrogen, dimethylaminomethyl, the morpholino methyl;

B is except that can not be for the H, and (I) is described for same compound.

Compound of the present invention (I) when A be six ring Japanese yew alkanol residues, when n is 0, water-soluble six ring Taxans have the structure of logical formula V:

Wherein:

B is except that can not be for the H, and all the other same compounds (I) are described, R ₅(IV) is described for same compound.

Another object of the present invention provides the preparation method of water-soluble taxane: Taxan (a) in the presence of alkali with

Reaction obtains 2,7 or 2 and 7 esters that all replace (b); (b) with

Reaction obtains water-soluble purpose product (I).

Reaction formula is:

Wherein:

R ' is a kind of among halogen, SM, the OM, and the same compound of M (I) is described;

R, X, X ', M ', the same compound of n (I) are described;

Y is a kind of in chlorine, bromine, the iodine.

Related alkali refers to a kind of in sodium hydride, potassium hydride KH, low-carbon (LC) sodium alkoxide, low-carbon (LC) potassium alcoholate, low-carbon (LC) lithium alkoxide or the organic amine among the above-mentioned preparation method.

Water-soluble taxane provided by the invention can be in the application in the preparation antitumor drug, and the dosage form of described medicine is oral preparations or injection formulations.

Water-soluble taxane good water solubility of the present invention need not be added tensio-active agent and oiliness auxiliary material during preparation, can directly make powder pin or transfusion; Because of it has good bioavailability, also can be made into oral preparations.Water-soluble taxane of the present invention can be used for preparing clinical treatment tumour patient's medicine.Water-soluble taxane of the present invention clinical application on the one hand is convenient, has increased patient's compliance on the other hand, therefore has remarkable advantages and marketable value.

Embodiment

The present invention is further described in conjunction with the embodiments.Present invention is described for following examples, and these examples only are can not be interpreted as limitation of the scope of the invention for explanation.

Synthetic (II-00) of embodiment 1 2-Mono Chloro Acetic Acid Japanese yew alcohol ester

In taxol (100mg 0.117mol) is dissolved in pyridine 3ml),, drip sym-dichloroacetic anhydride (40.05mg under the magnetic agitation at ice bath; 0.234mol), nitrogen protection keeps water-less environment; after dropwising, remove ice bath, reaction solution rises to room temperature gradually; 3h is stirred in argon shield down, after the some plate reacts completely, adds ethyl acetate and water; use ethyl acetate extraction, merge organic phase, wash with water 2-3 time again; the organic phase drying is filtered, and is concentrated into the dried 2-of obtaining Mono Chloro Acetic Acid Japanese yew alcohol ester (II-00).

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.81(CH，d，H)、3.37(CH，m，H)、3.38(CH，m，H)、4.01(CH，d，H)、4.34(CH2，s，2H)、4.43(CH，t，H)、5.05，4.80(CH2，m，2H)、5.51(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 2 taxols-2-(disodium thiophosphoryl sulfydryl) acetic ester (II-1)

In there-necked flask, once add phosphorodithioic acid sodium (3.92g, 0.02mol), 2-Mono Chloro Acetic Acid Japanese yew alcohol ester (g, 0.022mol) and distilled water 16ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips ethanol 26ml in solution, placement is spent the night, and gets solid.Wash 1 time with 4.5ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid taxol-2-(disodium thiophosphoryl sulfydryl) acetic ester (II-1), yield 95%.

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.65，1.55(CH，m，H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.67(CH，d，H)、2.78(CH，d，H)、3.38(CH，m，H)、3.52(CH，m，H)、4.43(CH，t，H)、4.49，4.24(CH，m，H)、5.51(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.66(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.00(2CH，m，2H)。

Synthetic (II-2) of embodiment 3 taxols-2-(disodium phosphinylidyne sulfydryl) acetic ester

In there-necked flask, once add sodium thiophosphate (0.072g, 0.2mmol), 2-Mono Chloro Acetic Acid Japanese yew alcohol ester (0.2g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, placement is spent the night, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid taxol-2-(disodium phosphinylidyne sulfydryl) acetic ester (II-2).

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.81(CH，d，H)、3.37(CH，m，H)、3.38(CH，m，H)、3.52(CH2，s，2H)、4.01(CH，d，H)、4.43(CH，t，H)、5.05，4.80(CH2，m，2H)、5.51(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthetic (II-3) of embodiment 4 taxols-2-(disodium phosphorus acyloxy) acetic ester

In there-necked flask, once add sodium phosphate (0.076g, 0.2mmol), 2-Mono Chloro Acetic Acid Japanese yew alcohol ester (0.27g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid taxol-2-(disodium phosphorus acyloxy) acetic ester (II-3).

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.81(CH，d，H)、3.37(CH，m，H)、3.38(CH，m，H)、4.01(CH，d，H)、4.43(CH，t，H)、4.99(CH2，s，2H)、5.05，4.80(CH2，m，2H)、5.51(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthetic (II-01) of embodiment 5 2-chloropropionic acid Japanese yew alcohol esters

(100mg 0.117mol) is dissolved in the pyridine (3ml), at ice bath, drips α-chlorpromazine chloride (29.7mg under the magnetic agitation with taxol; 0.234mol), nitrogen protection keeps water-less environment; after dropwising, remove ice bath, reaction solution rises to room temperature gradually; 3h is stirred in argon shield down, after the some plate reacts completely, adds ethyl acetate and water; use ethyl acetate extraction, merge organic phase, wash with water 2-3 time again; the organic phase drying is filtered, and is concentrated into the dried 2-of obtaining chloropropionic acid Japanese yew alcohol ester (II-01).

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.71(CH3，m，3H)、1.77(CH3，m，3H)、1.85，1.60(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.81(CH，d，H)、3.37(CH，m，H)、3.38(CH，m，H)、4.01(CH，d，H)、4.43(CH，t，H)、4.48(CH，t，H)、5.05，4.80(CH2，m，2H)、5.51(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthetic (II-4) of embodiment 6 α-disodium phosphorus acyloxy propionic acid Japanese yew alcohol ester

In there-necked flask, once add sodium phosphate (76.02g, 0.2mol), 2-chloropropionic acid Japanese yew alcohol ester (0.21g, 0.22mol) and distilled water 160ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 120ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 260ml in solution, placement is spent the night, and gets solid.Wash 1 time with 45ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid α-disodium phosphorus acyloxy propionic acid Japanese yew alcohol ester (II-4), and yield is 91.3%.

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.39(CH3，m，3H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.81(CH，d，H)、3.37(CH，m，H)、3.38(CH，m，H)、4.01(CH，d，H)、4.23(CH，t，H)、4.43(CH，t，H)、5.05，4.80(CH2，m，2H)、5.51(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthetic (II-5) of embodiment 7 α-disodium phosphinylidyne thiohydracrylic acid Japanese yew alcohol ester

In there-necked flask, once add sodium thiophosphate (0.072g, 0.2mmol), 2-chloropropionic acid Japanese yew alcohol ester (0.21g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, placement is spent the night, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid α-disodium phosphinylidyne thiohydracrylic acid Japanese yew alcohol ester (II-5), and yield is 92.6%.

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.59(CH3，m，3H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.81(CH，d，H)、3.37(CH，m，H)、3.38(CH，m，H)、3.54(CH，t，H)、4.01(CH，d，H)、4.43(CH，t，H)、5.05，4.80(CH2，m，2H)、5.51(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthetic (II-6) of embodiment 8 taxols-2-(disodium thiophosphoryl sulfydryl) propionic ester

In there-necked flask, once add phosphorodithioic acid sodium (3.92g, 0.02mol), 2-chloropropionic acid Japanese yew alcohol ester (0.21g, 0.022mol) and distilled water 16ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 26ml in solution, placement is spent the night, and gets solid.Wash 1 time with 4.5ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid taxol-2-(disodium thiophosphoryl sulfydryl) propionic ester (II-6), yield 95%.

Synthetic (II-02) of embodiment 9 alpha-chloro toluylic acid Japanese yew alcohol esters

With taxol (100mg; 0.117mol) be dissolved in the pyridine (3ml); at ice bath, and dropping chlorinated benzene Acetyl Chloride 98Min. under the magnetic agitation (44.23mg, 0.234mol); nitrogen protection; keep water-less environment, after dropwising, remove ice bath; reaction solution rises to room temperature gradually; 3h is stirred in argon shield down, after the some plate reacts completely, adds ethyl acetate and water; use ethyl acetate extraction; merge organic phase, wash 2-3 time the organic phase drying again with water; filter, be concentrated into the dried 2-of obtaining chlorobenzene acetic acid Japanese yew alcohol ester (II-02).

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.81(CH，d，H)、3.37(CH，m，H)、3.38(CH，m，H)、4.01(CH，d，H)、4.43(CH，t，H)、5.05，4.80(CH2，m，2H)、5.51(CH，s，H)、5.59(CH，t，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，d，2H)、7.26(4CH，m，4H)、7.32(2CH，m，2H)、7.44(CH，t，H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthetic (II-7) of embodiment 10 α-disodium phosphinylidyne sulfydryl toluylic acid Japanese yew alcohol ester

In there-necked flask, once add sodium thiophosphate (72.03g, 0.2mol), 2-chlorophenyl acetic acid Japanese yew alcohol ester (0.22g, 0.22mol) and distilled water 160ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 120ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 260ml in solution, placement is spent the night, and gets solid.Wash 1 time with 45ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid α-disodium phosphinylidyne sulfydryl toluylic acid Japanese yew alcohol ester (II-7), and yield is 91%.

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.81(CH，d，H)、3.37(CH，m，H)、3.38(CH，m，H)、4.01(CH，d，H)、4.43(CH，t?H)、4.65(CH，t，H)、5.05，4.80(CH2，m，2H)、5.51(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.06(2CH，d，2H)、7.12(2CH，d，2H)、7.25(CH，d，H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.34(2CH，d，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthetic (II-8) of embodiment 11 α-disodium phosphorus acyloxy toluylic acid Japanese yew alcohol ester

In there-necked flask, once add sodium phosphate (76.02g, 0.2mol), 2-chlorophenyl acetic acid Japanese yew alcohol ester (0.22g, 0.22mol) and distilled water 160ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 120ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 260ml in solution, place a moment, spends the night, and gets solid.Wash 1 time with 45ml alcohol, vacuum drying oven drying (30inchesHg, 45 ℃) 48 hours obtains white solid α-disodium phosphorus acyloxy toluylic acid Japanese yew alcohol ester (II-8), and yield is 91.4%.

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.81(CH，d，H)、3.37(CH，m，H)、3.38(CH，m，H)、4.01(CH，d，H)、4.43(CH，t，H)、5.05，4.80(CH2，m，2H)、5.43(CH，tH)、5.51(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，d，2H)、7.19(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.37(CH，t?H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 12 taxols-2-(disodium thiophosphoryl sulfydryl) phenylacetate (II-9)

In there-necked flask, once add phosphorodithioic acid sodium (3.92g, 0.02mol), 2-chlorophenyl acetic acid Japanese yew alcohol ester (0.22g, 0.022mol) and distilled water 16ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 26ml in solution, placement is spent the night, and gets solid.Wash 1 time with 4.5ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid taxol-2-(disodium thiophosphoryl sulfydryl) phenylacetate (II-9), yield 95%.

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.81(CH，d，H)、3.37(CH，m，H)、3.38(CH，m，H)、4.01(CH，d，H)、4.43(CH，t，H)、4.65(CH，t，H)、5.05，4.80(CH2，m，2H)、5.51(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.06(2CH，d，2H)、7.12(2CH，d，2H)、7.25(CH，d，H)、7.26(CH，m，H)、7.32(2CH，m，2H)、、7.34(2CH，d，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 13 2-Mono Chloro Acetic Acid Docetaxel esters (II-03)

With Docetaxel (94.52mg; 0.117mol) be dissolved in the pyridine (3ml); at ice bath, drip under the magnetic agitation sym-dichloroacetic anhydride (40.05mg, 0.234mol); nitrogen protection; keep water-less environment, after dropwising, remove ice bath; reaction solution rises to room temperature gradually; 3h is stirred in argon shield down, after the some plate reacts completely, adds ethyl acetate and water; use ethyl acetate extraction; merge organic phase, wash 2-3 time the organic phase drying again with water; filter, be concentrated into the synthetic of the dried 2-of obtaining Mono Chloro Acetic Acid Docetaxel ester (II-03).

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.40(3CH3，s，9H)、1.55，1.65(CH，m，H)、1.71(CH3，s，3H)、1.85，1.60(CH2，m，2H)、2.01(CH3，s，3H)、2.13，1.88(CH2，m，2H)、2.67(CH，m，H)、2.78(CH，q，H)、3.38(CH，t，H)、4.34(CH2，s，2H)、4.43(CH2，t，2H)、4.49，4.24(CH，d，H)、4.77(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，s，2H)、7.19(CH，m，H)、7.26(CH，d，H)、7.32(2CH，m，2H)、7.55(2CH，t，2H)、7.66(CH，m，H)、8.01(2CH，m，2H)。

Synthesizing of embodiment 14 Docetaxels-2-(disodium phosphinylidyne sulfydryl) acetic ester (II-10)

In there-necked flask, once add sodium thiophosphate (0.072g, 0.2mmol), 2-Mono Chloro Acetic Acid Docetaxel ester (0.195g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, leave standstill, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid Docetaxel-2-(disodium phosphinylidyne sulfydryl) acetic ester (II-10), and yield is 93.4%.

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.40(3CH3，s，9H)、1.55，1.65(CH，m，H)、1.71(CH3，s，3H)、1.85，1.60(CH2，m，2H)、2.01(CH3，s，3H)、2.13，1.88(CH2，m，2H)、2.67(CH，m，H)、2.78(CH，q，H)、3.38(CH，t，H)、3.52(CH2，s，2H)、4.43(CH2，t，2H)、4.49，4.24(CH，d，H)、4.77(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，s，2H)、7.19(CH，m，H)、7.26(CH，d，H)、7.32(2CH，m，2H)、7.55(2CH，t，2H)、7.66(CH，m，H)、8.01(2CH，m，2H)。

Synthesizing of embodiment 15 Docetaxels-2-(disodium phosphorus acyloxy) acetic ester (II-11)

In there-necked flask, once add sodium phosphate (0.076g, 0.2mmol), 2-Mono Chloro Acetic Acid Docetaxel ester (0.195g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, placement is spent the night, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid Docetaxel-2-(disodium phosphorus acyloxy) acetic ester (II-11), and yield is 92%.

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.40(3CH3，s，9H)、1.55，1.65(CH，m，H)、1.71(CH3，s，3H)、1.85，1.60(CH2，m，2H)、2.01(CH3，s，3H)、2.13，1.88(CH2，m，2H)、2.67(CH，m，H)、2.78(CH，q，H)、3.38(CH，t，H)、4.43(CH2，t，2H)、4.49，4.24(CH，d，H)、4.77(CH，s，H)、4.99(CH2，s，2H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，s，2H)、7.19(CH，m，H)、7.26(CH，d，H)、7.32(2CH，m，2H)、7.55(2CH，t，2H)、7.66(CH，m，H)、8.01(2CH，m，2H)。

Synthesizing of embodiment 16 Docetaxels-2-(disodium thiophosphoryl sulfydryl) acetic ester (II-12)

In there-necked flask, once add phosphorodithioic acid sodium (3.92g, 0.02mol), 2-Mono Chloro Acetic Acid Docetaxel ester (0.195g, 0.022mol) and distilled water 16ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 26ml in solution, placement is spent the night, and gets solid.Wash 1 time with 4.5ml alcohol, vacuum drying oven drying (30inchesHg, 45 ℃) 48 hours obtains white solid taxol-2-(disodium thiophosphoryl sulfydryl) phenylacetate (II-12), yield 95%.

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.40(3CH3，s，9H)、1.55，1.65(CH，m，H)、1.71(CH3，s，3H)、1.85，1.60(CH2，m，2H)、2.13，1.88(CH2，m，2H)、2.67(CH，m，H)、2.78(CH，q，H)、3.38(CH，t，H)、3.52(CH2，s，2H)、4.43(CH2，t，2H)、4.49，4.24(CH，d，H)、4.77(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，s，2H)、7.19(CH，m，H)、7.26(CH，d，H)、7.32(2CH，m，2H)、7.55(2CH，t，2H)、7.66(CH，m，H)、8.01(2CH，m，2H)。

Synthesizing of embodiment 17 2-chloropropionic acid Docetaxel esters (II-04)

With Docetaxel (94.5mg; 0.117mol) be dissolved in the pyridine (3ml); at ice bath, drip under the magnetic agitation α-chlorpromazine chloride (29.7mg, 0.234mol); nitrogen protection; keep water-less environment, after dropwising, remove ice bath; reaction solution rises to room temperature gradually; 3h is stirred in argon shield down, after the some plate reacts completely, adds ethyl acetate and water; use ethyl acetate extraction; merge organic phase, wash 2-3 time the organic phase drying again with water; filter, be concentrated into the dried 2-of obtaining chloropropionic acid Docetaxel ester (II-04).

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.40(3CH3，s，9H)、1.71(CH3，s，3H)、1.85，1.60(CH2，m，2H)、2.01(CH3，m，3H)、2.13，1.88(CH2，m，2H)、2.22(CH，m，H)、2.66(CH，m，H)、2.78(CH，q，H)、3.38(CH，t，H)、4.01(CH，s，H)、4.43(CH2，t，2H)、4.48(CH，s，H)、4.77(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，s，2H)、7.19(CH，m，H)、7.26(CH，d，H)、7.32(2CH，m，2H)、7.55(2CH，t，2H)、7.65(CH，m，H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 18 Docetaxels-2-(disodium phosphorus acyloxy) propionic ester (II-13)

In there-necked flask, once add sodium phosphate (0.076g, 0.2mmol), 2-chloropropionic acid Docetaxel ester (0.195g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, placement is spent the night, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid Docetaxel-2-(disodium phosphorus acyloxy) propionic ester (II-13), yield 91.8%.

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.39(CH3，s，3H)、1.40(3CH3，s，9H)、1.71(CH3，s，3H)、1.85，1.60(CH2，m，2H)、2.01(3CH，m，3H)、2.13，1.88(CH2，m，2H)、2.22(CH，m，H)、2.66(CH，m，H)、2.78(CH，q，H)、3.38(CH，t，H)、4.01(CH，s，H)、4.23(CH，s，H)、4.43(CH2，t，2H)、4.77(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，s，2H)、7.19(CH，m，H)、7.26(CH，d，H)、7.32(2CH，m，2H)、7.55(2CH，t，2H)、7.65(CH，m，H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 19 Docetaxels-2-(disodium phosphinylidyne sulfydryl) propionic ester (II-14)

In there-necked flask, once add sodium thiophosphate (0.072g, 0.2mmol), 2-chloropropionic acid Docetaxel ester (0.195g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inchesHg, 45 ℃) 48 hours obtains white solid Docetaxel-2-(disodium phosphinylidyne sulfydryl) propionic ester (II-14), yield 94%.

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.40(3CH3，s，9H)、1.59(CH3，s，3H)、1.71(CH3，s，3H)、1.85，1.60(CH2，m，2H)、2.01(CH3，m，3H)、2.13，1.88(CH2，m，2H)、2.22(CH，m，H)、2.66(CH，m，H)、2.78(CH，q，H)、3.38(CH，t，H)、3.54(CH，s，H)、4.01(CH，s，H)、4.43(CH2，t，2H)、4.77(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，s，2H)、7.19(CH，m，H)、7.26(CH，d，H)、7.32(2CH，m，2H)、7.55(2CH，t，2H)、7.65(CH，m，H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 20 Docetaxels-2-(disodium thiophosphoryl sulfydryl) propionic ester (II-15)

In there-necked flask, once add phosphorodithioic acid sodium (3.92g, 0.02mol), 2-chloropropionic acid Docetaxel ester (0.195g, 0.022mol) and distilled water 16ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 26ml in solution, place a moment, spends the night, and gets solid.Wash 1 time with 4.5ml alcohol, vacuum drying oven drying (30inchesHg, 45 ℃) 48 hours obtains white solid Docetaxel-2-(disodium thiophosphoryl sulfydryl) propionic ester (II-15), yield 95%.

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.40(3CH3，s，9H)、1.59(CH3，s，3H)、1.71(CH3，s，3H)、1.85，1.60(CH2，m，2H)、2.01(CH3，m，3H)、2.13，1.88(CH2，m，2H)、2.22(CH，m，H)、2.66(CH，m，H)、2.78(CH，q，H)、3.38(CH，t，H)、3.54(CH，s，H)、4.01(CH，s，H)、4.43(CH2，t，H)、4.77(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，s，2H)、7.19(CH，m，H)、7.26(CH，d，H)、7.32(2CH，m，2H)、7.55(2CH，t，2H)、7.65(CH，m，H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 21 2-chlorophenyl acetic acid Docetaxel esters (II-05)

With Docetaxel (94.5mg; 0.117mol) be dissolved in the pyridine (3ml); at ice bath, and dropping chlorinated benzene Acetyl Chloride 98Min. under the magnetic agitation (44.23mg, 0.234mol); nitrogen protection; keep water-less environment, after dropwising, remove ice bath; reaction solution rises to room temperature gradually; 3h is stirred in argon shield down, after the some plate reacts completely, adds ethyl acetate and water; use ethyl acetate extraction; merge organic phase, wash 2-3 time the organic phase drying again with water; filter, be concentrated into the dried 2-of obtaining chlorobenzene acetic acid Docetaxel ester (II-05).

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.40(3CH3，s，9H)、1.71(CH3，s，3H)、1.85，1.60(CH2，m，2H)、2.01(CH3，m，3H)、2.13，1.88(CH2，m，2H)、2.22(CH，m，H)、2.66(CH，m，H)、2.78(CH，q，H)、3.38(CH，t，H)、4.01(CH，s，H)、4.43(CH2，t，2H)、4.77(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，s，2H)、7.19(CH，m，H)、7.26(CH，d，H)、7.32(2CH，m，2H)、7.44(CH，m，H)、7.55(2CH，t，2H)、7.65(CH，m，H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 22 Docetaxels-2-(disodium phosphorus acyloxy) phenylacetate (II-16)

In there-necked flask, once add sodium phosphate (0.076g, 0.2mmol), 2-chlorobenzene acetic acid Docetaxel ester (0.22g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place a moment, spends the night, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inchesHg, 45 ℃) 48 hours obtains white solid Docetaxel-2-(disodium phosphorus acyloxy) phenylacetate (II-16), yield 94%.

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.40(3CH3，s，9H)、1.71(CH3，s，3H)、1.85，1.60(CH2，m，2H)、2.01(CH3，m，3H)、2.13，1.88(CH2，m，2H)、2.22(CH，m，H)、2.66(CH，m，H)、2.78(CH，q，H)、3.38(CH，t，H)、4.01(CH，s，H)、4.43(CH2，t，2H)、4.77(CH，s，H)、5.34(CH，m，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，s，2H)、7.19(CH，m，H)、7.26(CH，d，H)、7.32(2CH，m，2H)、7.37(CH，m，H)、7.55(2CH，t，2H)、7.65(CH，m，H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 23 Docetaxels-2-(disodium phosphinylidyne sulfydryl) phenylacetate (II-17)

In there-necked flask, once add sodium thiophosphate (0.072g, 0.2mmol), 2-chlorobenzene acetic acid Docetaxel ester (0.22g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place a moment, spends the night, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid Docetaxel-2-(disodium phosphinylidyne sulfydryl) phenylacetate (II-17), yield 92.8%.

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.40(3CH3，s，9H)、1.71(CH3，s，3H)、1.85，1.60(CH2，m，2H)、2.01(CH3，m，3H)、2.13，1.88(CH2，m，2H)、2.22(CH，m，H)、2.66(CH，m，H)、2.78(CH，q，H)、3.38(CH，t，H)、4.01(CH，s，H)、4.43(CH2，t，2H)、4.65(CH，t，H)、4.77(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.06(CH2，t，2H)、7.12(2CH，s，2H)、7.19(CH，m，H)、7.25(CH2，t，H)、7.26(CH，d，H)、7.32(2CH，m，2H)、7.34(2CH，m，2H)、7.55(2CH，t，2H)、7.65(CH，m，H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 24 Docetaxels-2-(disodium thiophosphoryl sulfydryl) phenylacetate (II-18)

In there-necked flask, once add phosphorodithioic acid sodium (3.92g, 0.02mol), 2-chlorobenzene acetic acid Docetaxel ester (0.22g, 0.022mol) and distilled water 16ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 26ml in solution, place a moment, spends the night, and gets solid.Wash 1 time with 4.5ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid Docetaxel-2-(disodium thiophosphoryl sulfydryl) phenylacetate (II-18), yield 93.2%.

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.40(3CH3，s，9H)、1.71(CH3，s，3H)、1.85，1.60(CH2，m，2H)、2.01(CH3，m，3H)、2.13，1.88(CH2，m，2H)、2.22(CH，m，H)、2.66(CH，m，H)、2.78(CH，q，H)、3.38(CH，t，H)、4.01(CH，s，H)、4.43(CH2，t，2H)、4.65(CH，t，H)、4.77(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.06(CH2，t，2H)、7.12(2CH，s，2H)、7.19(CH，m，H)、7.25(CH2，t，2H)、7.26(CH，d，H)、7.32(2CH，m，2H)、7.34(2CH，m，2H)、7.55(2CH，t，2H)、7.65(CH，m，H)、8.03(2CH，m，2H)。

Embodiment 25 2 ', 7-Mono Chloro Acetic Acid Japanese yew alcohol ester (II-06) synthetic

(100mg 0.117mol) is dissolved in the pyridine (3ml), at ice bath with taxol; drip sym-dichloroacetic anhydride (80.1mg under the magnetic agitation; 0.468mol), nitrogen protection keeps water-less environment; after dropwising; remove ice bath, reaction solution rises to room temperature gradually, and argon shield is stirred down and spent the night; second day some plate observing response situation; after reacting completely, add ethyl acetate and water, use ethyl acetate extraction; merge organic phase; wash with water 2-3 time, the organic phase drying is filtered again; be concentrated into and driedly obtain 2 ', 7-Mono Chloro Acetic Acid Japanese yew alcohol ester (II-06).

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.71(CH3，m，3H)、1.93，1.68(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.81(CH，d，H)、3.37(CH，m，H)、4.01(CH，d，H)、4.12(CH，m，H)、4.34(CH2，s，2H)、4.43(CH，t，H)、5.05，4.80(CH2，m，2H)、5.51(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Embodiment 26 taxols-2,7-two (disodium phosphinylidyne sulfydryl) acetic ester (II-19) synthetic

In there-necked flask, once add sodium thiophosphate (0.144g, 0.4mmol), 2 ', (0.22g is 0.22mmol) with distilled water 0.5ml for 7-Mono Chloro Acetic Acid Japanese yew alcohol ester, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, and the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction and rises gradually, be no more than 20 ℃, finish, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid taxol-2,7-two (disodium phosphinylidyne sulfydryl) acetic ester (II-19).

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.71(CH3，m，3H)、1.93，1.68(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.81(CH，d，H)、3.37(CH，m，H)、3.52(CH2，m，2H)、4.01(CH，d，H)、4.12(CH，m，H)、4.43(CH，t，H)、5.05，4.80(CH2，m，2H)、5.51(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Embodiment 27 taxols-2 ', 7-two (disodium phosphorus acyloxy) acetic ester (II-20) synthetic

In there-necked flask, once add sodium phosphate (0.152g, 0.4mmol), 2 ', (0.22g is 0.22mmol) with distilled water 0.5ml for 7-Mono Chloro Acetic Acid Japanese yew alcohol ester, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, and the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction and rises gradually, be no more than 20 ℃, finish, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place a moment, spends the night, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inchesHg, 45 ℃) 48 hours obtains white solid taxol-2 ', 7-two (disodium phosphorus acyloxy) acetic ester (II-20).

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.71(CH3，m，3H)、1.93，1.68(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.81(CH，d，H)、3.37(CH，m，H)、4.01(CH，d，H)、4.12(CH，m，H)、4.43(CH，t，H)、4.99(CH2，m，2H)、5.05，4.80(CH2，m，2H)、5.51(CH，s，H)、5.80(CH，m，H)、6.10(CH，s，H)、7.12(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Embodiment 28 taxols-2 ', 7-two (disodium thiophosphoryl sulfydryl) acetic ester (II-21) synthetic

In there-necked flask, once add phosphorodithioic acid sodium (0.078g, 0.4mmol), 2 ', (0.22g is 0.22mmol) with distilled water 0.5ml for 7-Mono Chloro Acetic Acid Japanese yew alcohol ester, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, and the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction and rises gradually, be no more than 20 ℃, finish, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid taxol-2 ', 7-two (disodium phosphorus acyloxy) acetic ester (II-21).

Synthesizing of embodiment 29 7-Mono Chloro Acetic Acid Japanese yew alcohol esters (II-07)

(100mg 0.117mol) is dissolved in the pyridine (3ml), at ice bath, drips sym-dichloroacetic anhydride (40.05mg under the magnetic agitation with taxol; 0.234mol), nitrogen protection keeps water-less environment; after dropwising, remove ice bath, reaction solution rises to room temperature gradually; 3h is stirred in argon shield down, after the some plate reacts completely, adds ethyl acetate and water; use ethyl acetate extraction, merge organic phase, wash with water 2-3 time again; the organic phase drying is filtered, and is concentrated into the dried 7-of obtaining Mono Chloro Acetic Acid Japanese yew alcohol ester (II-07).

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.71(CH3，m，3H)、1.93，1.68(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.81(CH，d，H)、3.37(CH，m，H)、4.01(CH，d，H)、4.12(CH，m，H)、4.34(CH2，m，2H)、4.43(CH，t，H)、5.05，4.80(CH2，m，2H)、5.06(CH，s，H)、5.51(CH，m，H)、5.59(CH，m，H)、7.12(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 30 taxols-7-two (disodium phosphinylidyne sulfydryl) acetic ester (II-22)

In there-necked flask, once add sodium thiophosphate (0.072g, 0.2mmol), 7-Mono Chloro Acetic Acid Japanese yew alcohol ester (0.2g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, placement is spent the night, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid taxol-7-(disodium phosphinylidyne sulfydryl) acetic ester (II-22).

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.71(CH3，m，3H)、1.93，1.68(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.81(CH，d，H)、3.37(CH，m，H)、3.52(CH2，m，2H)、4.01(CH，d，H)、4.12(CH，m，H)、4.43(CH，t，H)、5.05，4.80(CH2，m，2H)、5.06(CH，s，H)、5.51(CH，m，H)、5.59(CH，m，H)、7.12(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 31 taxols-7-(disodium phosphorus acyloxy) acetic ester (II-23)

In there-necked flask, once add sodium phosphate (0.076g, 0.2mmol), 7-Mono Chloro Acetic Acid Japanese yew alcohol ester (0.2g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place a moment, spends the night, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inchesHg, 45 ℃) 48 hours obtains white solid taxol-7-(disodium phosphorus acyloxy) acetic ester (II-23).

¹H-NMR(D6-DMSO-D2O)：δ1.21(2CH3，s，6H)、1.26(CH3，s，3H)、1.71(CH3，m，3H)、1.93，1.68(CH2，m，2H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.81(CH，d，H)、3.37(CH，m，H)、4.01(CH，d，H)、4.12(CH，m，H)、4.43(CH，t，H)、4.99(CH2，m，2H)、5.05，4.80(CH2，m，2H)、5.06(CH，s，H)、5.51(CH，m，H)、5.59(CH，m，H)、7.12(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 32 taxols-7-(disodium thiophosphoryl sulfydryl) acetic ester (II-24)

In there-necked flask, once add phosphorodithioic acid sodium (3.92g, 0.02mol), 7-Mono Chloro Acetic Acid Japanese yew alcohol ester (0.2g, 0.022mol) and distilled water 16ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 26ml in solution, place, and gets solid.Wash 1 time with 4.5ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid taxol-7-(disodium thiophosphoryl sulfydryl) acetic ester (II-24), yield 95%.

Embodiment 33 2 '-Mono Chloro Acetic Acid pentacycle taxane alcohol ester (III-00) synthetic

With pentacycle taxane (99.4mg; 0.117mmol) be dissolved in the pyridine (3ml); at ice bath, drip under the magnetic agitation sym-dichloroacetic anhydride (40.05mg, 0.234mol); nitrogen protection; keep water-less environment, after dropwising, remove ice bath; reaction solution rises to room temperature gradually; 3h is stirred in argon shield down, after the some plate reacts completely, adds ethyl acetate and water; use ethyl acetate extraction; merge organic phase, wash 2-3 time the organic phase drying again with water; filter, be concentrated into the dried 2 '-Mono Chloro Acetic Acid pentacycle taxane alcohol ester (III-00) that obtains.

¹H-NMR(D6-DMSO-D2O)：δ1.16(CH3，s，3H)、1.21(2CH3，s，6H)、1.41(CH3，s，3H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、1.99(CH3，s，3H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.66(CH，d，H)、2.78(CH，d，H)、3.15(CH，m，H)、3.90(CH，m，H)、4.01(CH，d，H)、4.34(CH2，m，2H)、4.43(CH，t，H)、4.57(CH，t，H)、5.80(CH，m，H)、6.10(CH，m，H)、7.12(2CH，d，2H)、7.19(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m2H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 34 pentacycle taxane alcohol-2 '-(disodium phosphorus acyloxy) acetic ester (III-1)

In there-necked flask, once add sodium phosphate (0.076g, 0.2mmol), 2 '-Mono Chloro Acetic Acid pentacycle taxane alcohol ester (0.2g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid pentacycle taxane alcohol-2 '-(disodium phosphorus acyloxy) acetic ester (III-1).

¹H-NMR(D6-DMSO-D2O)：δ1.16(CH3，s，3H)、1.21(2CH3，s，6H)、1.41(CH3，s，3H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、1.99(CH3，s，3H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.66(CH，d，H)、2.78(CH，d，H)、3.15(CH，m，H)、3.90(CH，m，H)、4.01(CH，d，H)、4.43(CH，t，H)、4.57(CH，t，H)、4.99(CH2，m，2H)、5.80(CH，m，H)、6.10(CH，m，H)、7.12(2CH，d，2H)、7.19(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 35 pentacycle taxane alcohol-2 '-(disodium phosphinylidyne sulfydryl) acetic ester (III-2)

In there-necked flask, once add sodium thiophosphate (0.072g, 0.2mmol), 2 '-Mono Chloro Acetic Acid pentacycle taxane alcohol ester (0.2g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inchesHg, 45 ℃) 48 hours obtains white solid pentacycle taxane alcohol-2 '-(disodium phosphinylidyne sulfydryl) acetic ester (III-2).

¹H-NMR(D6-DMSO-D2O)：δ1.16(CH3，s，3H)、1.21(2CH3，s，6H)、1.41(CH3，s，3H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、1.99(CH3，s，3H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.66(CH，d，H)、2.78(CH，d，H)、3.15(CH，m，H)、3.52(CH2，m，2H)、3.90(CH，m，H)、4.01(CH，d，H)、4.43(CH，t，H)、4.57(CH，t，H)、5.80(CH，m，H)、6.10(CH，m，H)、7.12(2CH，d，2H)、7.19(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 36 pentacycle taxane alcohol-2 '-(disodium thiophosphoryl sulfydryl) acetic ester (III-3)

In there-necked flask, once add phosphorodithioic acid sodium (3.92g, 0.02mol), 2 '-Mono Chloro Acetic Acid pentacycle taxane alcohol ester (0.2g, 0.022mol) and distilled water 16ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 26ml in solution, place a moment, spends the night, and gets solid.Wash 1 time with 4.5ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid pentacycle taxane alcohol-2 '-(disodium thiophosphoryl sulfydryl) acetic ester (III-3), yield 92%.

Embodiment 37 2 ', 7-Mono Chloro Acetic Acid pentacycle taxane alcohol derivate ester (III-01) synthetic

(82.6mg 0.117mol) is dissolved in the pyridine (3ml), at ice bath with the pentacycle taxane alcohol derivate; drip sym-dichloroacetic anhydride (80.1mg under the magnetic agitation; 0.468mol), nitrogen protection keeps water-less environment; after dropwising; remove ice bath, reaction solution rises to room temperature gradually, and argon shield is stirred down and spent the night; second day some plate observing response situation; after reacting completely, add ethyl acetate and water, use ethyl acetate extraction; merge organic phase; wash with water 2-3 time, the organic phase drying is filtered again; be concentrated into dried 2 ', 7-Mono Chloro Acetic Acid pentacycle taxane alcohol derivate ester (III-01).

¹H-NMR(D6-DMSO-D2O)：δ1.16(CH3，s，3H)、1.21(2CH3，s，6H)、1.41(CH3，s，3H)、1.71(CH3，m，3H)、1.93，1.68(CH2，m，2H)、1.99(CH3，s，3H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.66(CH，d，H)、2.78(CH，d，H)、3.89(CH，m，H)、3.90(CH，m，H)、4.01(CH，d，H)、4.34(2CH2，t，4H)、4.43(CH，t，H)、4.57(CH，t，H)、5.80(CH，m，H)、6.06(CH，m，H)、6.33(CH，m，H)、6.39(CH，m，H)、7.12(2CH，d，2H)、7.19(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.56(CH，t，H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Embodiment 38 pentacycle taxane alcohol derivate-2 ', 7-two (disodium phosphorus acyloxy) acetic ester (III-4) synthetic

In there-necked flask, once add sodium phosphate (0.152g, 0.4mmol), 2 ', (0.19g is 0.22mmol) with distilled water 0.4ml for 7-Mono Chloro Acetic Acid pentacycle taxane alcohol derivate ester, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, and the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction and rises gradually, be no more than 20 ℃, finish, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place a moment, spends the night, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid pentacycle taxane alcohol derivate-2 ', 7-two (disodium phosphorus acyloxy) acetic ester (III-4).

¹H-NMR(D6-DMSO-D2O)：δ1.16(CH3，s，3H)、1.21(2CH3，s，6H)、1.41(CH3，s，3H)、1.71(CH3，m，3H)、1.93，1.68(CH2，m，2H)、1.99(CH3，s，3H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.66(CH，d，H)、2.78(CH，d，H)、3.89(CH，m，H)、3.90(CH，m，H)、4.01(CH，d，H)、4.43(CH，t，H)、4.57(CH，t，H)、4.99(2CH2，t，4H)、5.80(CH，m，H)、6.06(CH，m，H)、6.33(CH，m，H)、6.39(CH，m，H)、7.12(2CH，d，2H)、7.19(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.56(CH，t，H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Embodiment 39 pentacycle taxane alcohol derivate-2 ', 7-two (disodium phosphinylidyne sulfydryl) acetic ester (III-5) synthetic

In there-necked flask, once add sodium thiophosphate (0.144g, 0.4mmol), 2 ', (0.19g is 0.22mmol) with distilled water 0.4ml for 7-Mono Chloro Acetic Acid pentacycle taxane alcohol derivate ester, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, and the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction and rises gradually, be no more than 20 ℃, finish, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place a moment, spends the night, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid pentacycle taxane alcohol derivate-2 ', 7-two (disodium phosphinylidyne sulfydryl) acetic ester (III-5).

¹H-NMR(D6-DMSO-D2O)：δ1.16(CH3，s，3H)、1.21(2CH3，s，6H)、1.41(CH3，s，3H)、1.71(CH3，m，3H)、1.93，1.68(CH2，m，2H)、1.99(CH3，s，3H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.66(CH，d，H)、2.78(CH，d，H)、3.52(2CH2，t，4H)、3.89(CH，m，H)、3.90(CH，m，H)、4.01(CH，d，H)、4.43(CH，t，H)、4.57(CH，t?H)、5.80(CH，m，H)、6.06(CH，m，H)、6.33(CH，m，H)、6.39(CH，m，H)、7.12(2CH，d，2H)、7.19(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.56(CH，t?H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Embodiment 40 2 '-Mono Chloro Acetic Acid pentacycle taxane alcohol derivate ester (III-02) synthetic

With pentacycle taxane alcohol derivate (108.7mg; 0.117mol) be dissolved in the pyridine (3ml); at ice bath, drip under the magnetic agitation sym-dichloroacetic anhydride (40.05mg, 0.234mol); nitrogen protection; keep water-less environment, after dropwising, remove ice bath; reaction solution rises to room temperature gradually; 3h is stirred in argon shield down, after the some plate reacts completely, adds ethyl acetate and water; use ethyl acetate extraction; merge organic phase, wash 2-3 time the organic phase drying again with water; filter, be concentrated into the dried 2 '-Mono Chloro Acetic Acid pentacycle taxane alcohol derivate ester (III-02) that obtains.

¹H-NMR(D6-DMSO-D2O)：δ1.16(CH3，s，3H)、1.21(2CH3，s，6H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、1.99(CH3，s，3H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.66(CH，d，H)、2.78(CH，d，H)、3.15(CH，t，H)、3.72(CH3，t，3H)、3.90(CH，m，H)、4.01(CH，d，H)、4.34(CH2，t，2H)、4.43(CH，t，H)、4.57(CH，t，H)、5.80(CH，m，H)、6.10(CH，m，H)、6.18(CH，t，H)、6.70(2CH，t，2H)、7.08(2CH，t，2H)、7.12(2CH，d，2H)、7.19(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.56(CH，t，H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 41 pentacycle taxane alcohol derivate-2 '-(disodium phosphorus acyloxy) acetic ester (III-6)

In there-necked flask, once add sodium phosphate (0.076g, 0.2mmol), 2 '-Mono Chloro Acetic Acid pentacycle taxane alcohol derivate ester (0.22g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place a moment, spends the night, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inchesHg, 45 ℃) 48 hours obtains white solid pentacycle taxane alcohol derivate-2 '-(disodium phosphorus acyloxy) acetic ester (III-6).

¹H-NMR(D6-DMSO-D2O)：δ1.16(CH3，s，3H)、1.21(2CH3，s，6H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、1.99(CH3，s，3H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.66(CH，d，H)、2.78(CH，d，H)、3.15(CH，t，H)、3.72(CH3，t，3H)、3.90(CH，m，H)、4.01(CH，d，H)、4.43(CH，t，H)、4.57(CH，t，H)、4.99(CH2，t，2H)、5.80(CH，m，H)、6.10(CH，m，H)、6.18(CH，t，H)、6.70(2CH，t，2H)、7.08(2CH，t，2H)、7.12(2CH，d，2H)、7.19(2CH，d，2H)、7.26(CH，m，H)、7.32(2CH，m，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.56(CH，t，H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Embodiment 42 2 '-Mono Chloro Acetic Acid pentacycle taxane alcohol derivate ester (III-03) synthetic

With pentacycle taxane alcohol derivate (107.5mg; 0.117mol) be dissolved in the pyridine (3ml); at ice bath, drip under the magnetic agitation sym-dichloroacetic anhydride (40.05mg, 0.234mol); nitrogen protection; keep water-less environment, after dropwising, remove ice bath; reaction solution rises to room temperature gradually; 3h is stirred in argon shield down, after the some plate reacts completely, adds ethyl acetate and water; use ethyl acetate extraction; merge organic phase, wash 2-3 time the organic phase drying again with water; filter, be concentrated into the dried 2 '-Mono Chloro Acetic Acid pentacycle taxane alcohol derivate ester (III-03) that obtains.

¹H-NMR(D6-DMSO-D2O)：δ1.16(CH3，s，3H)、1.21(2CH3，s，6H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、1.99(CH3，s，3H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.66(CH，d，H)、2.78(CH，d，H)、3.15(CH，t，H)、3.72(CH3，t，3H)、3.90(CH，m，H)、4.01(CH，d，H)、4.34(CH2，m，2H)、4.43(CH，t，H)、4.57(CH，t，H)、5.80(CH，m，H)、6.06(CH，m，H)、6.18(CH，t，H)、6.33(CH，m，H)、6.39(CH，m，H)、6.70(2CH，t，2H)、7.08(2CH，t，2H)、7.19(2CH，d，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.56(CH，t，H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 43 pentacycle taxane alcohol derivate-2 '-(disodium phosphorus acyloxy) acetic ester (III-7)

In there-necked flask, once add sodium phosphate (0.076g, 0.2mmol), 2 '-Mono Chloro Acetic Acid pentacycle taxane alcohol derivate ester (0.219g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inchesHg, 45 ℃) 48 hours obtains white solid pentacycle taxane alcohol derivate-2 '-(disodium phosphorus acyloxy) acetic ester (III-7).

¹H-NMR(D6-DMSO-D2O)：δ1.16(CH3，s，3H)、1.21(2CH3，s，6H)、1.71(CH3，m，3H)、1.85，1.60(CH2，m，2H)、1.99(CH3，s，3H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.66(CH，d，H)、2.78(CH，d，H)、3.15(CH，t，H)、3.72(CH3，t，3H)、3.90(CH，m，H)、4.01(CH，d，H)、4.43(CH，t，H)、4.57(CH，t，H)、4.99(CH2，t，2H)、5.80(CH，m，H)、6.06(CH，m，H)、6.18(CH，t，H)、6.33(CH，m，H)、6.39(CH，m，H)、6.70(2CH，t，2H)、7.08(2CH，t，2H)、7.19(2CH，d，2H)、7.54(2CH，m，2H)、7.55(2CH，m，2H)、7.56(CH，t，H)、7.65(CH，m，H)、7.70(CH，m，H)、7.86(2CH，m，2H)、8.03(2CH，m，2H)。

Synthesizing of embodiment 44 2-Mono Chloro Acetic Acid five rings Japanese yew alcohol esters (III-04)

With water-soluble paclitaxel (103.19mg; 0.117mol) be dissolved in the pyridine (3ml); at ice bath, drip under the magnetic agitation sym-dichloroacetic anhydride (40.05mg, 0.234mol); nitrogen protection; keep water-less environment, after dropwising, remove ice bath; reaction solution rises to room temperature gradually; 3h is stirred in argon shield down, after the some plate reacts completely, adds ethyl acetate and water; use ethyl acetate extraction; merge organic phase, wash 2-3 time the organic phase drying again with water; filter, be concentrated into the dried 2-of obtaining Mono Chloro Acetic Acid six ring Japanese yew alcohol esters (III-04).

¹H-NMR(D6-DMSO-D2O)：δ1.16(CH3，s，3H)、1.21(2CH3，s，6H)、1.40(2CH3，s，6H)、1.71(CH3，m，3H)、1.49，1.24(CH2，m，2H)、1.70，1.45(CH2，m，2H)、1.99(CH3，s，3H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.27(2CH3，s，6H)、2.66(CH，d，H)、2.78(CH，d，H)、2.79，2.54(CH2，m，2H)、3.90(CH，m，H)、4.01(CH，d，H)、4.34(CH2，m，2H)、4.43(CH，t，H)、4.57(CH，t，H)、5.13(CH，t，H)、5.80(CH，m，H)、6.10(CH，m，H)、7.27(2CH3，t，6H)、7.53(2CH，d，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、8.03(2CH，m，2H)、8.41(2CH，m，2H)。

Synthesizing of embodiment 45 five rings taxol-2-(disodium phosphorus acyloxy) acetic ester (III-8)

In there-necked flask, once add sodium phosphate (0.076g, 0.2mmol), 2-Mono Chloro Acetic Acid water-soluble paclitaxel ester (0.21g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid five rings taxol-2-(disodium phosphorus acyloxy) acetic ester (III-8), yield 93%.

¹H-NMR(D6-DMSO-D2O)：δ1.16(CH3，s，3H)、1.21(2CH3，s，6H)、1.40(2CH3，s，6H)、1.71(CH3，m，3H)、1.49，1.24(CH2，m，2H)、1.70，1.45(CH2，m，2H)、1.99(CH3，s，3H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.27(2CH3，s，6H)、2.66(CH，d，H)、2.78(CH，d，H)、2.79，2.54(CH2，m，2H)、3.90(CH，m，H)、4.01(CH，d，H)、4.43(CH，t，H)、4.57(CH，t，H)、4.99(CH2，m，2H)、5.13(CH，t，H)、5.80(CH，m，H)、6.10(CH，m，H)、7.27(2CH3，t，6H)、7.53(2CH，d，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、8.03(2CH，m，2H)、8.41(2CH，m，2H)。

Embodiment 46 five rings taxol-2-(disodium phosphinylidyne sulfydryl) acetic ester (III-9)

In there-necked flask, once add sodium thiophosphate (0.072g, 0.2mmol), 2-Mono Chloro Acetic Acid water-soluble paclitaxel ester (0.21g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inchesHg, 45 ℃) 48 hours obtains white solid five rings taxol-2-(disodium phosphinylidyne sulfydryl) acetic ester (III-9), yield 92%.

¹H-NMR(D6-DMSO-D2O)：δ1.16(CH3，s，3H)、1.21(2CH3，s，6H)、1.40(2CH3，s，6H)、1.71(CH3，m，3H)、1.49，1.24(CH2，m，2H)、1.70，1.45(CH2，m，2H)、1.99(CH3，s，3H)、2.01(2CH3，s，6H)、2.13，1.88(CH2，m，2H)、2.27(2CH3，s，6H)、2.66(CH，d，H)、2.78(CH，d，H)、2.79，2.54(CH2，m，2H)、3.52(CH2，m，2H)、3.90(CH，m，H)、4.01(CH，d，H)、4.43(CH，t，H)、4.57(CH，t，H)、5.13(CH，t，H)、5.80(CH，m，H)、6.10(CH，m，H)、7.27(2CH3，t，6H)、7.53(2CH，d，2H)、7.55(2CH，m，2H)、7.65(CH，m，H)、8.03(2CH，m，2H)、8.41(2CH，m，2H)。

Synthesizing of embodiment 47 five rings taxol-2-(disodium thiophosphoryl sulfydryl) acetic ester (III-10)

In there-necked flask, once add phosphorodithioic acid sodium (3.92g, 0.02mol), 2-Mono Chloro Acetic Acid water-soluble paclitaxel ester (0.21g, 0.022mol) and distilled water 16ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 26ml in solution, place, and gets solid.Wash 1 time with 4.5ml alcohol, vacuum drying oven drying (30inchesHg, 45 ℃) 48 hours obtains white solid five rings taxol-2-(disodium thiophosphoryl sulfydryl) acetic ester (III-10), yield 93.6%.

Synthesizing of embodiment 48 2-Mono Chloro Acetic Acids six ring Taxan alcohol esters (IV-00)

With six ring Japanese yew alkanol (98.2mg; 0.117mol) be dissolved in the pyridine (3ml); at ice bath, drip under the magnetic agitation sym-dichloroacetic anhydride (40.05mg, 0.234mol); nitrogen protection; keep water-less environment, after dropwising, remove ice bath; reaction solution rises to room temperature gradually; 3h is stirred in argon shield down, after the some plate reacts completely, adds ethyl acetate and water; use ethyl acetate extraction; merge organic phase, wash 2-3 time the organic phase drying again with water; filter, be concentrated into the dried 2-of obtaining Mono Chloro Acetic Acid six ring Taxan alcohol esters (IV-00).

¹H-NMR (D6-DMSO-D2O): δ 0.23,0.02 (CH2, m, 2H), 1.21 (2CH3, s, 6H), 1.41 (2CH3, s, 6H), 1.42 (CH3, s, 3H), 1.65,1.40 (CH2, m, 2H), 1.71 (CH3, m, 3H), 1.99 (CH3, s, 3H), 2.01 (2CH3, s, 6H), 2.13,1.88 (CH2, m, 2H), 2.66 (CH, d, H), 2.78 (CH, d, H), 3.90 (CH, m, H), 4.01 (CH, d, H), 4.34 (CH2, t, 2H), 4.43 (CH, t, H), 4.57 (CH, t, H), 5.80 (CH, m, H), 6.10 (CH, m, H), 7.19 (CH, t, H), 7.39 (CH, t, H), 7.54 (2CH, m, 2H), 7.55 (CH, t, H), 7.65 water (CH, t, H), 7.70 (CH, t, H), 7.86 (CH, m, H), 8.03 (2CH, m, 2H), 8.31 (CH, t, H), 8.37 (2CH, m, 2H).

Synthesizing of embodiment 49 6 ring Japanese yew alkanol-2-(disodium phosphorus acyloxy) acetic ester (IV-1)

In there-necked flask, once add sodium phosphate (0.076g, 0.2mmol), 2-Mono Chloro Acetic Acid six ring Taxan alcohol ester (0.2g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inches Hg, 45 ℃) 48 hours obtains white solid six ring Japanese yew alkanol-2-(disodium phosphorus acyloxy) acetic ester (IV-1), yield 93.4%.

¹H-NMR (D6-DMSO-D2O): δ 0.23,0.02 (CH2, m, 2H), 1.21 (2CH3, s, 6H), 1.41 (2CH3, s, 6H), 1.42 (CH3, s, 3H), 1.65,1.40 (CH2, m, 2H), 1.71 (CH3, m, 3H), 1.99 (CH3, s, 3H), 2.01 (2CH3, s, 6H), 2.13,1.88 (CH2, m, 2H), 2.66 (CH, d, H), 2.78 (CH, d, H), 3.90 (CH, m, H), 4.01 (CH, d, H), 4.43 (CH, t, H), 4.57 (CH, t, H), 4.99 (CH2, t, 2H), 5.80 (CH, m, H), 6.10 (CH, m, H), 7.19 (CH, t, H), 7.39 (CH, t, H), 7.54 (2CH, m, 2H), 7.55 (CH, t, H), 7.65 water (CH, t, H), 7.70 (CH, t, H), 7.86 (CH, m, H), 8.03 (2CH, m, 2H), 8.31 (CH, t, H), 8.37 (2CH, m, 2H).

Synthesizing of embodiment 50 6 ring Japanese yew alkanol-2-(disodium phosphinylidyne sulfydryl) acetic ester (IV-2)

In there-necked flask, once add sodium thiophosphate (0.072g, 0.2mmol), 2-Mono Chloro Acetic Acid six ring Taxan alcohol ester (0.2g, 0.22mmol) and distilled water 0.4ml, stir, under the frozen water cooling, temperature drops to about 15 ℃ naturally in the flask, the limit drips dimethyl sulfoxide (DMSO) (DMSO) 0.12ml temperature of reaction rises gradually, is no more than 20 ℃, finishes, continue to be stirred to and react completely, obtain product solution; Continuation drips 95% ethanol 0.3ml in solution, place, and gets solid.Wash 1 time with 0.1ml alcohol, vacuum drying oven drying (30inchesHg, 45 ℃) 48 hours obtains white solid six ring Japanese yew alkanol-2-(disodium phosphinylidyne sulfydryl) acetic ester (IV-2), yield 93.8%.

¹H-NMR (D6-DMSO-D2O): δ 0.23,0.02 (CH2, m, 2H), 1.21 (2CH3, s, 6H), 1.41 (2CH3, s, 6H), 1.42 (CH3, s, 3H), 1.65,1.40 (CH2, m, 2H), 1.71 (CH3, m, 3H), 1.99 (CH3, s, 3H), 2.01 (2CH3, s, 6H), 2.13,1.88 (CH2, m, 2H), 2.66 (CH, d, H), 2.78 (CH, d, H), 3.52 (CH2, t, 2H), 3.90 (CH, m, H), 4.01 (CH, d, H), 4.43 (CH, t, H), 4.57 (CH, t, H), 5.80 (CH, m, H), 6.10 (CH, m, H), 7.19 (CH, t, H), 7.39 (CH, t, H), 7.54 (2CH, m, 2H), 7.55 (CH, t, H), 7.65 water (CH, t, H), 7.70 (CH, t, H), 7.86 (CH, m, H), 8.03 (2CH, m, 2H), 8.31 (CH, t, H), 8.37 (2CH, m, 2H).

Embodiment 51 tumor promotions are measured.

Adopt the MTT reduction method, with human breast carcinoma (MCF-7), people's nonsmall-cell lung cancer (PG-49) cell suspending liquid (5 * 10 ⁷/ L), being inoculated in 96 orifice plates, every hole 200 μ L after 24 hours, add Compound I I-1 of the present invention, III-1, III-9IV-1, II-10 respectively, and three density components of each compound are not 1 * 10 ^-9, 1 * 10 ^-7, 1 * 10 ^-5Mol/L, individual concentration is given 8 multiple holes, not dosing of control group.Other establishes blank group (having only substratum, acellular).Continue to cultivate 48 hours, add MTT (5mg/ml) 20 μ L, the centrifuging and taking precipitation adds DMSO 200 μ L after 4 hours, and lucifuge vibration 5 minutes is with the light absorption value (A) at full-automatic enzyme mapping 570nm place.Calculate cell inhibitory rate=(A contrast-A test)/(A contrast-A blank) * 100%.

Table 1

Embodiment 52 solubility tests: get Compound I I-1 of the present invention, III-1, III-9, IV-1, II-10,, measure dissolved sample size in the water of every 100ml, the results are shown in Table 2 respectively by the solubility test of middle traditional Chinese medicines.

Table 2

Compound	Solubleness (mg/100ml)
Compound	Solubleness (mg/100ml)	Taxol	??0.004
??II-1	??39	Taxol	??0.004
??II-1	??39	??III-1	??15
??III-9	??30	??III-1	??15
??III-9	??30	??IV-1	??47
??II-10	??51	??IV-1	??47

Embodiment 53 investigates the stability of sample in the aqueous solution:

II-1, III-1, IV-1 is soluble in water respectively, and can sampling to detect free paclitaxel, investigate its stability in the aqueous solution at regular intervals, the results are shown in Table 3.

Table 3

Time (my god)	??II-1	??III-1	??IV-1
Time (my god)	??II-1	??III-1	??IV-1	0 day	??-	??-	??-
10 days	??-	??-	??-	0 day	??-	??-	??-
10 days	??-	??-	??-	30 days	??-	??-	??-
60 days	??-	??-	??-	30 days	??-	??-	??-
60 days	??-	??-	??-	90 days	??-	??-	??-

Annotate: "-" expression does not detect taxol through tlc and high performance liquid phase.

Compound of the present invention is stable in 90 days in the aqueous solution, the free taxane compounds can not occur.

Embodiment 54 investigates samples in free taxane compounds situation in blood:

II-1, III-1, III-9, IV-1, II-10 are dissolved in respectively in the fresh dog blood, concentration is 1.0mg/ml, jolting 5 minutes, get 200 μ L, mark docetaxel solution (10.0mg/ml) 10 μ L, ether 3ml, acetate buffer (PH=5) 20 μ L in adding, vortex mixed 3 minutes, centrifugal (5000r/min) 5 minutes, get that nitrogen dries up in 25 ℃ of water-baths of organic stratification, residue is with 100 μ L dissolve with methanol, get 10 μ L and inject liquid chromatograph, calculate II-1, III-1, III-9, IV-1, the pairing taxane content of II-10.The result is referring to table 4.

Table 4

Compound of the present invention is hydrolyzed to corresponding Taxan fast in animal blood.

Claims

1. a water-soluble taxane has general structure (I)

Wherein:

B and B ' be H or

In one, except that B and B ' can not be the H simultaneously, B and B ' are identical or different, in the formula:

R is H, contain the fat alkane of 2 to 7 carbon,

In one, R wherein ₀Be one in H, F, Cl, Br, oxy radical, the nitrogen-containing group, X and X ' are among O, the S, M or M ' be H, Na, K, Cs, Li, NH4, Ca, Mg, CH3, CF3, C2H5, C3H7, C4H9, C6H5, CH2C6H5, in one.

2. a kind of water-soluble taxane according to claim 1 is characterized in that, when the A of described compound (I) be Fourth Ring Japanese yew alkanol residue, when n is 1, its water-soluble Fourth Ring Taxan has the structure of general formula (II):

Wherein:

R ₁Be C ₆H ₅-or (CH ₃) ₃Among the CO-one;

R ₂Be H or CH ₃Among the CO-one;

The same compound of B and B ' (I) is described.

3. a kind of water-soluble taxane according to claim 1 is characterized in that, when the A of described compound (I) be pentacycle taxane alcohol residue, when n is 1, its water-soluble pentacycle taxane has the structure of general formula (III):

Wherein:

R ₃Be

In one;

R ₄Be

In one;

The same compound of B and B ' (I) is described.

4. a kind of water-soluble taxane according to claim 1 is characterized in that, when the A of described compound (I) be pentacycle taxane alcohol residue, when n is 0, its water-soluble pentacycle taxane has the structure of general formula (IV):

Wherein:

R ₅Be halogen atom or alkoxyl group with 1 to 6 carbon atom;

R ₆Be in hydrogen, dimethylaminomethyl, the morpholino methyl;

B is except that can not be for the H, and (I) is described for same compound.

5. a kind of water-soluble taxane according to claim 1 is characterized in that, when the A of described compound (I) be six ring Japanese yew alkanol residues, when n is 0, water-soluble six ring Taxans have the structure of logical formula V:

Wherein:

6. the preparation method of a kind of water-soluble taxane according to claim 1 is characterized in that, realizes by following steps:

Taxan (a) in the presence of alkali with

Reaction obtains 2,7 or 2 and 7 esters that all replace (b), the ester of replacement (b) and

Reaction obtains water-soluble purpose product (I), and reaction formula is:

Wherein:

R ' is a kind of among halogen, SM, the OM, and M is described with the compound (I) of claim 1;

R, X, X ', M ', n are described with the compound (I) of claim 1;

Y is a kind of in chlorine, bromine, the iodine.

7. the preparation method of a kind of water-soluble taxane according to claim 6 is characterized in that, described alkali is a kind of in sodium hydride, potassium hydride KH, low-carbon (LC) sodium alkoxide, low-carbon (LC) potassium alcoholate, low-carbon (LC) lithium alkoxide or the organic amine.

8. the application of a kind of water-soluble taxane according to claim 1 in the preparation antitumor drug is characterized in that the dosage form of described medicine is oral preparations or injection formulations.