CN103421036B - A kind of Cabazitaxel intermediate and its preparation method and application - Google Patents

Abstract

The invention discloses a kind of Cabazitaxel intermediate and its preparation method and application.Described intermediate has a chemical structural formula shown in formula I:TES in formula is the abbreviation of triethyl silicane.The preparation of described intermediate includes step B in following synthetic route or step A～step B:

Description

A kind of Cabazitaxel intermediate and its preparation method and application

Technical field

The present invention relates to a kind of Cabazitaxel intermediate and its preparation method and application, belong to technical field of medicine synthesis.

Background technology

Carcinoma of prostate is male's common cancer, regular incidence in elderly men, the U.S. be in addition to skin carcinoma second largest common Male cancer.

Cabazitaxel (Cabazitaxel, trade name Jevtana) is that Sanofi-Aventis company (Sanofi-Aventis SA) researches and develops Plant microtubule inhibitors, previously suffer from containing Docetaxel therapeutic scheme hormone refractory metastatic prostate cancer with prednisone combination treatment The new drug of person, particular chemical formula is as follows:

Cabazitaxel is a kind of paclitaxel analogs, and chemical constitution is sufficiently complex, and structure has 11 chiral carbon atoies, with Anti-cancer medicine paclitaxel is similar with Docetaxel structure, is a kind of white to canescence compound, the most same paclitaxel of mechanism of action The same with docetaxel, it is to strengthen tubulin polymerization effect and suppression microtubule depolymerization effect, results in stable non-functional Microtubule fasolculus, thus tumoricidal mitosis.Compared with other taxanes medicine, Cabazitaxel generation drug resistance Property probability low, can be used for treat Multidrug resistance tumor, this medicine can pass through blood brain barrier (Blood Brain Barrier, BBB) in addition.

Cabazitaxel is controlled with prednisone (Prednisone) combination by FDA approval on June 17th, 2010 because its curative effect is remarkable Treat advanced prostate cancer, and in U.S.'s list marketing；In April, 2011, on EU member country and several other countries are the most granted City.The listing of Jevtana, brings more therapy apparatus meeting to prostate patient.

The compound patent application WO9630355 that main technique the is Sanofi-Aventis company report of synthesis Cabazitaxel at present Synthesis technique, concrete synthetic route is as follows:

Above-mentioned route is that to use 10-DAB (formula 1 compound) be raw material, to 7 and 10 upper hydroxyl selectivity methyl Obtaining 7 after change, 10-dimethoxy-10-baccatin III, then he obtains mesh after matching the condensation of one of side chain, hydrolysis with various polyenoid Mark product Cabazitaxel (7,10-dimethoxy docetaxel), this technological reaction route length, severe reaction conditions, complex process, Multistep needs that column chromatography purification, yield be relatively low, total recovery is only 5%, it is clear that do not meet industrialization production requirements.

Chinese patent application CN201110162562 discloses the synthetic method of a kind of Cabazitaxel, and the method is former with isoborneol Material, prepares, through five step reactions, (3R, 4S)-beta-lactam that tert-butyldimethyl silyl (TBS) is protected；Under alkali effect, 10-is taken off In acetyl baccatin III (formula 1 compound), C-7 and C-10 position hydroxyl carries out methyl-etherified reaction and obtains 7,10-dimethoxy-10-bar Card fourth III, (3R, the 4S)-beta-lactam with TBS protection carries out esterification the most in the basic conditions, and guarantor is sloughed in last acidolysis Protecting base and obtain Cabazitaxel (Cabazitaxel), concrete synthetic route is as follows:

Disclosed in this patent route, five steps synthesize (3R, the 4S)-beta-lactam of TBS protection, and total recovery only has 16%, the tert-butyl group of employing Dimethylchlorosilane is expensive；Three-step reaction total recovery followed by also only has 17%.Therefore, this synthesis technique entirety is received Rate is less than 3%, and multistep used post to separate and mixed solvent recrystallization method, needs to use substantial amounts of organic solvent, produces Waste water and solvent slop are more, cause production cost to increase, and cause environmental pollution, and whole reaction time consumption is longer, and reaction is received Rate is relatively low, and product purity is the highest, it is also apparent that commercial Application requirement can not be met.

Chinese patent application CN201110298014.2 also discloses that the preparation method of a kind of Cabazitaxel, and the method is directly with 10- Deacetyl baccatin III (formula 1 compound) is raw material, first C-7 and the C-10 position to 10-DAB (formula 1 compound) Hydroxyl carries out methyl-etherified reaction and obtains 7,10-dimethoxy-10-baccatin III (formula 2 compound), the most in the basic conditions with (3R, 4S)-beta-lactam that ethoxyethyl group (EE) is protected carries out esterification, and last acidolysis is sloughed protection group and obtained Cabazitaxel (Cabazitaxel), concrete synthetic route is as follows:

Three step synthetic reaction conditions in this patent route are harsh, and poor selectivity, yield is low, finished product purity is low, is also not suitable for industry Change production requirement.

Summary of the invention

In view of the foregoing defects the prior art has and problem, it is an object of the invention to provide a kind of for synthesizing in Cabazitaxel Mesosome and preparation method thereof and the application in preparing Cabazitaxel of this intermediate, to realize utilizing raw material cheap and easy to get, low one-tenth The purpose of this synthesis of high purity Cabazitaxel, meets the industrial production demand of Cabazitaxel.

In order to realize foregoing invention purpose, the technical solution used in the present invention is as follows:

A kind of Cabazitaxel intermediate, has a chemical structural formula shown in formula I:

TES in formula is the abbreviation of triethyl silicane (Triethylsilane).

A kind of preparation method of described intermediate, including step B in following synthetic route or step A～step B:

Wherein: step A refers to that formula 1 compound and methylating reagent carry out methylation reaction and obtain formula 2 compound；Step B refers to formula 2 compounds and formula 3 compound carry out condensation reaction and obtain described intermediate I.

As a kind of preferred version, the operation of described step A is as follows: first by molten for 10-DAB (formula 1 compound) In organic solvent A, the methylating reagent with excess carries out methylation reaction the most in the basic conditions.

As further preferred scheme, described organic solvent A is nitrogen heterocyclic ring kind solvent or phosphoric acid ester solvent.

As further preferred version, described nitrogen heterocyclic ring kind solvent is N-Methyl pyrrolidone (NMP), N-ethyl pyrrole Pyrrolidone (NEP), 1,3-dimethyl-2-imidazolinone (DMI) or pyridine；Described phosphoric acid ester solvent is triethyl phosphate.

As further preferred version, described organic solvent A has been also added with ether solvent, benzene kind solvent, acetone, Any one solvent in dimethyl sulfoxide (DMSO), dimethylformamide (DMF) or dimethyl acetylamide (DMA), and described The volume that adds of solvent is less than the 50% of organic solvent A cumulative volume.

As further preferred version, described ether solvent is oxolane or dioxane；Described benzene kind solvent is first Benzene.

As further preferred scheme, the alkaline condition described in step A refers in the presence of organic base or inorganic base, described Organic base be triethylamine, diethylamine or pyridine；Described inorganic base be sodium hydride, calcium hydride, sodium tert-butoxide, potassium tert-butoxide, Potassium carbonate, potassium bicarbonate, sodium carbonate or sodium bicarbonate.

As further preferred scheme, the methylating reagent described in step A is dimethyl sulfate, trimethyl orthoformate, iodine Methane or bromomethane.

As further preferred scheme, the methylating reagent described in step A and 10-DAB (formula 1 compound) Mol ratio be (2.0～30.0): 1, more preferably (3.0～6.0): 1.

As a kind of preferred version, the operation of described step B is as follows: be first suspended in absolute ether kind solvent by formula 2 compound, Then cool to-40～-50 DEG C, add organic base or inorganic base；Insulated and stirred 0.5～after 1.5 hours add formula 3 compound, Finish continuation insulated and stirred 10～60 minutes；Naturally it is warmed up to 0～30 DEG C, continues stirring and terminate to reaction；Carry out post processing.

As further preferred scheme, described absolute ether kind solvent refers to anhydrous tetrahydro furan or anhydrous dioxane.

As further preferred scheme, described organic base is hexamethyldisiloxane base lithium (LiHMDS), hexamethyl two silicon nitrogen Sodium alkyl (NaHMDS), hexamethyldisiloxane base potassium (KHMDS) or n-BuLi (n-BuLi)；Described inorganic base is NaH, KH or CaH₂。

As further preferred scheme, described formula 3 compound is (1.0～5.0) with the mol ratio of formula 2 compound: 1, further It is preferably (1.1～1.5): 1.

As further preferred scheme, described post-processing operation is as follows: reaction terminates, and reactant liquor is cooled to-5～-15 DEG C, Dropping saturated aqueous ammonium chloride；Separatory, aqueous phase is extracted with ethyl acetate；Combined ethyl acetate extract, uses saturated aqueous common salt Washing；Anhydrous sodium sulfate is dried；Concentrating under reduced pressure；The light yellow solid 30% methanol aqueous solution recrystallization that will obtain；Filter, Washing, vacuum drying.

The intermediate of the present invention application in preparing Cabazitaxel is as follows: hydrolyze de-in acid condition by described intermediate I Going triethyl silicane protection group, obtain Cabazitaxel, reaction equation is as follows:

As a kind of preferred version, described intermediate I is hydrolyzed in acid condition and sloughs triethyl silicane protection group and prepare kappa His operation of match is as follows: first described intermediate I is dissolved in suitable organic solvent B, then cools to 0～5 DEG C, dropping acid Solution, drips complete insulated and stirred and terminates to reaction；Carry out post processing.

As further preferred scheme, described organic solvent B is ethanol or ethyl acetate.

As further preferred scheme, described acid solution be aqueous hydrochloric acid solution, hydrogen chloride methanol solution, ethanol solution of hydrogen chloride, Hydrochloride/ethyl acetate, acetic acid methanol solution or vinyl alcohol solution.

As further preferred version, the pH value of described acid solution is 1～3.

As further preferred scheme, described post-processing operation is as follows: reaction terminates, and is warming up to room temperature；Add deionized water, Continue stirring 1～3 hour, separate out white solid, filter；With 30% methanol aqueous solution recrystallization；Filtration, washing, vacuum It is dried；Or, described post-processing operation is as follows: reaction terminates, and removes 1/3 in reactant liquor～the solvent of 2/3 volume under reduced pressure； Residue is cooled to-5～5 DEG C, continues stirring 1～3 hour；Filter；With 30% methanol aqueous solution recrystallization；Filter, wash Wash, be vacuum dried.

Compared with prior art, the present invention has a following remarkable result:

1) applying intermediate of the present invention to synthesize Cabazitaxel, have reaction condition gentle, simple to operate, yield height (rubs Your yield is up to more than 80%) etc. advantage, especially, only need recrystallization the most just can obtain HPLC purity and reach more than 99% Cabazitaxel end-product, meets industrialization production requirements.

2) preparation method of described intermediate is simple, and reaction condition is gentle, and the raw material of use is cheap and easy to get, and often step mole is received Rate all can reach more than 80%, and the HPLC purity of described intermediate reaches more than 97.5%.

In a word, the present invention can realize utilizing raw material cheap and easy to get, the purpose of low cost synthesis of high purity Cabazitaxel, can meet The large-scale industrial production demand of Cabazitaxel, Suitable commercial is applied, is had practical value.

Detailed description of the invention

Below in conjunction with embodiment, the present invention is described in further detail and completely.

Formula 3 compound used in embodiment is commercially available, it is possible to reference to Tetrahedron, 1992,48,6985-7012 or Tetrahedron, 1996,52,209-224 or Ojima I.et al., Chirality, 2000,12,431-441 or Ojima I.et al., Described in the documents such as Bioorg.Med.Chem.2003,11,2867-2888 or CN201010177213, method is prepared.

Embodiment 1: prepare intermediate of the present invention

Step A:

Under argon shield, 10-DAB (formula 1 compound) 10.9g (20mmol, commercial) is dissolved in 100mL N-first In base ketopyrrolidine (NMP)；It is cooled to-30 DEG C, adds sodium hydride 1.68g (70mmol), insulated and stirred 10～20 minutes；Drip Add iodomethane 11.36g (80mmol), drip complete insulated and stirred 3 hours；Warm naturally to room temperature, stirring reaction 6～8 hours, TLC Detection (developing solvent is methylene chloride/methanol=25/1, V/V) raw material reaction is complete, reactant liquor is cooled to 0 DEG C, then drips 50mL Saturated aqueous ammonium chloride；Dripping and finish, stirring is lower adds 500mL diisopropyl ether, and solid slowly separates out, and finishes continuation stirring 1 hour, Filter, obtain light yellow solid；With 30% methanol aqueous solution making beating；Filter；50 DEG C are vacuum dried 8 hours；Gained white solid Being formula 2 compound, altogether 9.6g (16.74mmol, molar yield 83.7%), HPLC purity is 96.1%.

LC-MS:[M+1]=573, [M+23]=595；

¹H NMR (300MHz, DMSO) δ: 8.11-8.02 (m, 2H), 7.72 (t, J=7.3Hz, 1H), 7.62 (t, J=7.4 Hz,2H),5.43(d,J=7.1Hz,1H),5.37(d,J=4.5Hz,1H),5.03(d,J=8.5Hz,1H),4.80(s,1H), 4.70(b,1H),4.47(s,1H),4.09(q,J=8.2Hz,2H),3.92–3.76(m,2H),3.35(s,3H),3.28(s,3H), 2.80–2.64(m,1H),2.26(s,3H),2.23(m,2H),2.03(s,3H),1.57(s,3H),1.50(m,1H),0.99(s, 6H)。

Step B:

Under argon shield, formula 2 compound 9.6g (16.74mmol) is suspended in 100mL anhydrous tetrahydro furan, be cooled to-40～ -50 DEG C, the LiHMDS tetrahydrofuran solution of dropping 25.1mL 1mol/L, drips complete insulated and stirred 1 hour；Dropping formula 3 chemical combination Oxolane (80mL) solution of thing 7.6g (20.1mmol), drips complete insulated and stirred 0.5 hour, is naturally warmed up to 0 DEG C, continues to stir Mixing 2 hours, TLC detection (developing solvent is petrol ether/ethyl acetate=3/1, V/V) raw material reaction is complete, is cooled down by reactant liquor To-10 DEG C, dripping 100mL saturated aqueous ammonium chloride, separatory, aqueous phase 300mL × 2 ethyl acetate extract 2 times；Close And acetic acid ethyl acetate extract, wash 1 time with 300mL saturated aqueous common salt；Anhydrous sodium sulfate is dried；It is evaporated to do pale yellow Color solid；With 30% methanol aqueous solution recrystallization；Filter；50 DEG C are vacuum dried 8 hours；Gained white solid is the present invention Intermediate I, altogether 14.12g (14.88mmol, molar yield 88.9%), HPLC purity is 98.3%.

LC-MS:[M+1]=950, [M+23]=972；

¹H NMR(300MHz,CDCl₃) δ: 8.15 8.06 (m, 2H), 7.59 (m, 1H), 7.48 (t, J=7.5Hz, 2H), 7.42–7.33(m,2H),7.32–7.27(m,3H),6.29(t,J=8.5Hz,1H),5.66(d,J=7.1Hz,1H),5.50(d,J =9.1Hz,1H),5.29(b,1H),5.00(d,J=7.8Hz,1H),4.81(s,1H),4.54(d,J=2.0Hz,1H),4.32(d, J=8.3Hz,1H),4.19(d,J=8.4Hz,1H),3.86-3.93(m,2H),3.45(s,3H),3.30(s,3H),2.66-2.76(m, 1H),2.55(s,3H),2.31-2.40(m,1H),1.93(d,3H),1.76-1.86(m,1H),1.72(s,3H),1.67(s,2H),1.33 (s,9H),1.24(s,3H),1.20(s,3H),0.77-0.49(m,9H),0.27-0.49(m,6H)。

Embodiment 2: prepare intermediate of the present invention

Step A:

Under argon shield, 10-DAB (formula 1 compound) 10.9g (20mmol, commercial) is dissolved in 60mL N-ethyl In ketopyrrolidine (NEP) and 30mL oxolane；It is cooled to-30 DEG C, adds potassium tert-butoxide 4.5g (40mmol), insulated and stirred 10～20 minutes；Dropping trimethyl orthoformate 4.24g (40mmol), drips complete insulated and stirred 3 hours；Warm naturally to room temperature, Stirring reaction 8～10 hours, TLC detection (developing solvent is methylene chloride/methanol=25/1, V/V) raw material reaction is complete, will reaction Liquid is cooled to 0 DEG C, then dropping 50mL saturated aqueous ammonium chloride；Dripping and finish, stirring is lower adds 500mL methyl tertiary butyl ether(MTBE), Solid slowly separates out, and finishes continuation stirring 1 hour, filters, obtain light yellow solid；With 30% methanol aqueous solution making beating；Filter； 50 DEG C are vacuum dried 8 hours；Gained white solid is formula 2 compound, altogether 9.4g (16.44mmol, molar yield 82.2%), HPLC purity is 95.6%.

Step B:

Under argon shield, formula 2 compound 9.4g (16.44mmol) is suspended in 100mL anhydrous dioxane, be cooled to-40～ -50 DEG C, it is dividedly in some parts 0.8g (33.3mmol) sodium hydride, finishes insulated and stirred 1 hour；Dropping formula 3 compound 9.3g (24.66mmol) Dioxane (80mL) solution, drip complete insulated and stirred 0.5 hour, naturally be warmed up to 20 DEG C, continue to stir 1～2 hour, TLC detection (developing solvent is petrol ether/ethyl acetate=3/1, V/V) raw material reaction is complete, and reactant liquor is cooled to-10 DEG C, drips Adding 100mL saturated aqueous ammonium chloride, separatory, aqueous phase 200ml × 2 ethyl acetate extract 2 times；Combined ethyl acetate extracts Take liquid, wash 1 time with 300ml saturated aqueous common salt；Anhydrous sodium sulfate is dried；It is evaporated to do to obtain light yellow solid；With 30% Methanol aqueous solution recrystallization；Filter；50 DEG C are vacuum dried 8 hours；Gained white solid is intermediate I of the present invention, altogether 13.46g (14.19mmol, molar yield 86.3%), HPLC purity is 98.7%.

Embodiment 3: prepare intermediate of the present invention

Step A:

Under argon shield, 10-DAB (formula 1 compound) 5.5g (10mmol) is dissolved in 60mL pyridine and 40mL In toluene；It is cooled to-30 DEG C, adds sodium hydride 1.0g (41.7mmol), insulated and stirred 10～20 minutes；Dropping bromomethane 3.8g (40mmol), drips complete insulated and stirred 3 hours；Warm naturally to room temperature, stirring reaction 6～8 hours, TLC detection (exhibition Opening agent is methylene chloride/methanol=25/1, V/V) raw material reaction is complete, and reactant liquor is cooled to 0 DEG C, and then dropping 50mL is saturated Aqueous ammonium chloride solution；Dripping and finish, stirring is lower adds 300mL diisopropyl ether, and solid slowly separates out, and finishes continuation stirring 1 hour, mistake Filter, a small amount of toluene drip washing obtains light yellow solid；With 20% methanol aqueous solution making beating；Filter；50 DEG C are vacuum dried 8 hours；Institute Obtaining white solid and be formula 2 compound, altogether 4.51g (7.89mmol, molar yield 78.9%), HPLC purity is 97.6%.

Step B:

Under argon shield, formula 2 compound 4.51g (7.89mmol) is suspended in 50mL anhydrous dioxane, be cooled to-40～ -50 DEG C, the NaHMDS dioxane solution of dropping 15.78mL 1mol/L, drip complete insulated and stirred 1 hour；Dropping formula 3 is changed Dioxane (60mL) solution of compound 5.95g (15.78mmol), drips complete insulated and stirred 0.5 hour, is naturally warmed up to 30 DEG C, Continuing stirring 1～2 hour, TLC detection (developing solvent is petrol ether/ethyl acetate=3/1, V/V) raw material reaction is complete, will be anti- Answer liquid to be cooled to-10 DEG C, drip 50mL saturated aqueous ammonium chloride, separatory, aqueous phase 100mL × 2 ethyl acetate extractions 2 Secondary；Combined ethyl acetate extract, washs 1 time with 100mL saturated aqueous common salt；Anhydrous sodium sulfate is dried；It is evaporated to do Obtain light yellow solid；With 30% methanol aqueous solution recrystallization；Filter；50 DEG C are vacuum dried 8 hours；Gained white solid is Intermediate I of the present invention, altogether 6.55g (6.90mmol, molar yield 87.5%), HPLC purity is 98.3%.

Embodiment 4: prepare intermediate of the present invention

Step A:

Under argon shield, 10-DAB (formula 1 compound) 5.5g (10mmol) is dissolved in 60mL N-crassitude In ketone (NMP) and 60mL acetone；It is cooled to-30 DEG C, adds potassium carbonate 5.5g (50mmol), insulated and stirred 10～20 minutes； Dropping dimethyl sulfate 7.57g (60mmol), drips complete insulated and stirred 2 hours；Warm naturally to 50 DEG C, stirring reaction 8 hours, TLC detection (developing solvent is methylene chloride/methanol=25/1, V/V) raw material reaction is complete, reactant liquor is cooled to 0 DEG C, then drips Add 50mL saturated aqueous ammonium chloride；Dripping and finish, stirring is lower adds 300mL diisopropyl ether, and solid slowly separates out, and finishes and continues to stir Mixing 1 hour, filter, a small amount of acetone drip washing obtains light yellow solid；With 20% methanol aqueous solution making beating；Filter；50 DEG C of vacuum are done Dry 8 hours；Gained white solid is formula 2 compound, altogether 4.6g (8.05mmol, molar yield 80.5%), HPLC purity It is 96.7%.

Step B:

Under argon shield, formula 2 compound 4.6g (8.05mmol) is suspended in 50mL anhydrous dioxane, is cooled to-40～-50 DEG C, the butyl lithium hexane solution of dropping 9.66mL 2.5mol/L, drips complete insulated and stirred 1 hour；Dropping formula 3 compound Dioxane (50mL) solution of 3.96g (10.5mmol), drips complete insulated and stirred 0.5 hour, is naturally warmed up to 20 DEG C, continues to stir Mixing 1～2 hour, TLC detection (developing solvent is petrol ether/ethyl acetate=3/1, V/V) raw material reaction is complete, and reactant liquor is cold But arriving-10 DEG C, drip 50mL saturated aqueous ammonium chloride, separatory, aqueous phase 100ml × 2 ethyl acetate extract 2 times；Close And acetic acid ethyl acetate extract, wash 1 time with 100mL saturated aqueous common salt；Anhydrous sodium sulfate is dried；It is evaporated to do pale yellow Color solid；With 30% methanol aqueous solution recrystallization；Filter；50 DEG C are vacuum dried 8 hours；Gained white solid is the present invention Intermediate I, altogether 6.38g (6.72mmol, molar yield 83.5%), HPLC purity is 97.6%.

Embodiment 5: utilize above-mentioned intermediate I to synthesize Cabazitaxel

Under argon shield, intermediate I 14.12g (14.88mmol) that embodiment 1 prepares is dissolved in 300mL ethanol, is cooled to 0～5 DEG C, dropping 20mL concentration is the ethanol solution of hydrogen chloride of 5mol/L；Dripping complete insulated and stirred to react 2 hours, TLC examines Survey (developing solvent is petrol ether/ethyl acetate=1/1, V/V) raw material reaction complete, be warming up to room temperature, add 500mL deionization Water, continues stirring 2 hours, separates out white solid；Filter；With 30% methanol aqueous solution recrystallization；Filter；50 DEG C of vacuum are done Dry 12 hours；Obtaining Cabazitaxel 10.9g (13.05mmol, molar yield 87.7%), HPLC purity is 99.2%.

LC-MS:[M+1]=836, [M+1]=858；

¹H NMR(300MHz,CDCl₃) δ: 8.09 (d, J=7.2Hz, 2H), 7.60 (t, J=7.4Hz, 1H), 7.48 (t, J= 7.5Hz,2H),7.42–7.35(m,4H),7.32(m,1H),6.20(t,J=8.5Hz,1H),5.62(d,J=7.0Hz,1H), 5.45(d,J=9.3Hz,1H),5.26(d,J=8.7Hz,1H),4.97(d,J=8.0Hz,1H),4.79(s,1H),4.62(b,1H), 4.29(d,J=8.3Hz,1H),4.16(d,J=8.4Hz,1H),3.92–3.75(m,2H),3.45(s,3H),3.30(s,3H), 2.64-2.74(m,1H),2.36(s,3H),2.26-2.29(m,2H),1.87(d,J=1.0Hz,3H),1.84–1.73(m,1H), 1.71(s,3H),1.68(s,1H),1.35(s,9H),1.20(d,J=2.2Hz,6H)。

Embodiment 6: utilize above-mentioned intermediate I to synthesize Cabazitaxel

Under argon shield, intermediate I 13.46g (14.19mmol) that embodiment 2 prepares is dissolved in 260mL ethyl acetate, cold But to 0～5 DEG C, dropping 20mL concentration is the Hydrochloride/ethyl acetate of 5mol/L；Drip complete insulated and stirred to react 2 hours, TLC detection (developing solvent is petrol ether/ethyl acetate=1/1, V/V) raw material reaction is complete, removes 120～150mL under reduced pressure molten Agent, residue is cooled to 0 DEG C, continues stirring 2 hours；Filter；With 30% methanol aqueous solution recrystallization；Filter；50 DEG C true Empty dry 12 hours；Obtaining Cabazitaxel 10.5g (12.03mmol, molar yield 84.8%), HPLC purity is 99.5%.

Embodiment 7: utilize above-mentioned intermediate I to synthesize Cabazitaxel

Under argon shield, intermediate I 6.55g (6.90mmol) that embodiment 3 prepares is dissolved in 100mL ethanol, be cooled to 0～ 5 DEG C, dropping 20mL concentration is the aqueous hydrochloric acid solution of 2mol/L；Dripping complete insulated and stirred to react 2 hours, TLC detection (launches Agent is petrol ether/ethyl acetate=1/1, V/V) raw material reaction is complete, is warming up to room temperature, adds 300mL deionized water, continue Stir 2 hours, separate out white solid；Filter；With 30% methanol aqueous solution recrystallization；Filter；50 DEG C of vacuum drying 12 are little Time；Obtaining Cabazitaxel 4.87g (5.84mmol, molar yield 84.6%), HPLC purity is 99.2%.

Embodiment 8: utilize above-mentioned intermediate I to synthesize Cabazitaxel

Under argon shield, intermediate I 6.38g (6.72mmol) that embodiment 4 prepares is dissolved in 100mL ethanol, be cooled to 0～ 5 DEG C, dropping 20mL concentration is the vinyl alcohol solution of 1mol/L；Drip complete insulated and stirred to react 2 hours, TLC detection (exhibition Opening agent is petrol ether/ethyl acetate=1/1, V/V) raw material reaction is complete, is warming up to room temperature, and add 300mL deionized water, continue Continuous stirring 2 hours, separates out white solid；Filter；With 30% methanol aqueous solution recrystallization；Filter；50 DEG C of vacuum drying 12 Hour；Obtaining Cabazitaxel 4.86g (5.83mmol, molar yield 86.8%), HPLC purity is 99.3%.

Finally be necessary described herein, above example only in order to technical scheme to be described and the unrestricted present invention, Although the present invention being described in detail with reference to preferred embodiment, it will be understood by those within the art that, can be to sending out Bright technical scheme is modified or equivalent, and without deviating from the spirit and scope of technical solution of the present invention, it all should be contained In scope of the presently claimed invention.

Claims (13)

1. a preparation method for Cabazitaxel intermediate, described Cabazitaxel intermediate has a chemical structural formula shown in formula I:

TES in formula is the abbreviation of triethyl silyl；Described method Comprise the steps B:

Its Being characterised by, the operation of described step B is as follows: be first suspended in absolute ether kind solvent by formula 2 compound, then cool to-40～ -50 DEG C, add organic base or inorganic base；Insulated and stirred 0.5～after 1.5 hours add formula 3 compound, finish continuation insulated and stirred 10～60 minutes；Naturally it is warmed up to 0～30 DEG C, continues stirring and terminate to reaction；Carry out post processing.

Preparation method the most according to claim 1, it is characterised in that described method also comprises the steps A:

It is characterized in that, described step A Operating as follows: be first dissolved in organic solvent A by formula 1 compound, the methylating reagent with excess is carried out the most in the basic conditions Methylation reaction.

Preparation method the most according to claim 2, it is characterised in that: described organic solvent A is that nitrogen heterocyclic ring class is molten Agent or phosphoric acid ester solvent.

Preparation method the most according to claim 3, it is characterised in that: described nitrogen heterocyclic ring kind solvent is N-methyl pyrrole Pyrrolidone, N-ethyl pyrrolidone, 1,3-dimethyl-2-imidazolinone or pyridine；Described phosphoric acid ester solvent is tricresyl phosphate second Ester.

Preparation method the most according to claim 2, it is characterised in that: described organic solvent A has been also added with ethers Any one solvent in solvent, benzene kind solvent, acetone, dimethyl sulfoxide, dimethylformamide or dimethyl acetylamide, and The volume that adds of described solvent is less than the 50% of organic solvent A cumulative volume.

Preparation method the most according to claim 5, it is characterised in that: described ether solvent is oxolane or dioxy Six rings；Described benzene kind solvent is toluene.

Preparation method the most according to claim 2, it is characterised in that: the alkaline condition described in step A refers to having In the presence of machine alkali or inorganic base；Described organic base is triethylamine, diethylamine or pyridine；Described inorganic base is sodium hydride, hydrogen Change calcium, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, potassium bicarbonate, sodium carbonate or sodium bicarbonate.

Preparation method the most according to claim 2, it is characterised in that: the methylating reagent described in step A is sulphuric acid Dimethyl ester, trimethyl orthoformate, iodomethane or bromomethane.

Preparation method the most according to claim 2, it is characterised in that: the methylating reagent described in step A and formula 1 The mol ratio of compound is (2.0～30.0): 1.

Preparation method the most according to claim 1, it is characterised in that: described absolute ether kind solvent refers to anhydrous tetrahydrochysene Furan or anhydrous dioxane.

11. preparation methoies according to claim 1, it is characterised in that: described organic base is hexamethyldisiloxane base Lithium, hexamethyldisiloxane base sodium, hexamethyldisiloxane base potassium or n-BuLi；Described inorganic base be NaH, KH or CaH₂。

12. preparation methoies according to claim 1, it is characterised in that: described formula 3 compound rubs with formula 2 compound Your ratio is (1.0～5.0): 1.

13. preparation methoies according to claim 1, it is characterised in that described post-processing operation is as follows: reaction terminates, Reactant liquor is cooled to-5～-15 DEG C, drips saturated aqueous ammonium chloride；Separatory, aqueous phase is extracted with ethyl acetate；Merge acetic acid Ethyl ester extract, washs with saturated aqueous common salt；Anhydrous sodium sulfate is dried；Concentrating under reduced pressure；By the light yellow solid that obtains with 30% Methanol aqueous solution recrystallization；Filter, wash, be vacuum dried.