CN103012328B - Method for preparing second-generation taxol anticancer drug Cabazitaxel - Google Patents

Method for preparing second-generation taxol anticancer drug Cabazitaxel Download PDF

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CN103012328B
CN103012328B CN201110287081.4A CN201110287081A CN103012328B CN 103012328 B CN103012328 B CN 103012328B CN 201110287081 A CN201110287081 A CN 201110287081A CN 103012328 B CN103012328 B CN 103012328B
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reaction
cabazitaxel
protecting group
reagent
xrp6258
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CN103012328A (en
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李英霞
刘珂
王军飞
丁宁
张伟
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WUXI TARGET DRUG RESEARCH Co Ltd
Fudan University
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WUXI TARGET DRUG RESEARCH Co Ltd
Fudan University
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention belongs to the field of medicament synthesis, and relates to a method for synthesizing a second-generation taxol anticancer drug Cabazitaxel. The method comprises obtaining a key intermediate (II): a 10-deacetyl baccatin III (I) with C-7 and C-10 hydroxy-methylthio-methylene and C-13 hydroxy-oxidization, completing a de-methylthio operation for C-13 carbonyl and C-7 and C-10 methylthio methylene (MTM) of the compound II by a one-pot method to obtain a nucleus (IV) of an XRP6258, connecting the nucleus with various side chains, and then removing side chain protecting groups to obtain the product Cabazitaxel (V). The method has advantages of high efficiency in the preparation process, simple process, high yield, relatively low cost and easy operation, and is suitable for large-scale production and preparation of anti-cancer drugs XRP6258.

Description

A kind of method preparing s-generation paclitaxel kind anti-cancer drugs Cabazitaxel
Technical field
The invention belongs to pharmaceutical synthesis field; relate to the method for synthesis s-generation taxanes PTS Cabazitaxel (XRP6258); be specifically related to a kind of novel method of 10-deacetylation bar card fourth III (I) for starting raw material synthesis XRP6258 (V); described method has the advantages such as preparation process efficiency is high, technique is simple, yield is high, cost is lower, easy handling, is suitable for large-scale manufacture anticarcinogen XRP6258.
Background technology
The star molecule of taxol (Paclitaxel) world today antitumor drug, it is mainly used in treatment ovarian cancer, the esophageal carcinoma, urinary tract transfer epithelial cancer, G. cephalantha, mammary cancer, nonsmall-cell lung cancer, maligna solid tumor and some other solid tumor clinically, evident in efficacy to treatment Metastatic carcinoma in the ovary, mammary cancer especially, be acknowledged as very rising antitumor drug.But taxol is the same with other chemotherapeutics, it is for multidrug resistance (MDR) tumour almost non-activity, and this is also the important factor that taxol medication causes chemotherapy failure.Thus, develop and still keep the taxane class of anti-cancer agents thing of curative effect to be the study hotspot of domestic and international pharmaceutical science man for multidrug resistance of tumor always.
Cabazitaxel (XRP6258) is the bearing taxanes researched and developed by French Sanofi-Aventis company, and its constructional feature is modified by two for C-7, C-10 position hydroxyl of docetaxel methyl-etherified.Cabazitaxel is the weak substrate of P-gp, thus than taxol with docetaxel is easier passes through hemato encephalic barrier (BBB).In June, 2010, Cabazitaxel obtains FDA Priority Review status approval listing by III phase clinical study smoothly because its curative effect is remarkable, the medicine of late period, hormone antagonist type prostate cancer is treated, also for the advanced prostate cancer patients to the invalid even aggravation of docetaxel as first-selection.Clinical studies show XRP6258 medication obviously can extend the survival time of tumour patient, makes patient's mean survival time reach 15.1 months.Except prostate cancer, XRP6258 also may become the new selection of other malignant tumours for the treatment of.
At present, the semisynthesis of XRP6258 has been reported, and mainly contains two synthetic routes:
(1). cling to Ka Ting (10-DAB) for initiator to remove acetyl, with methyl iodide or methyl sulfate for alkylating reagent, with the reagent such as sodium hydride, potassium hydride KH, n-Butyl Lithium, LiHMDS, NaHMDS for alkali, a step completes C-7 position and the two methyl-etherified (WO9925704) of C-10 position hydroxyl:
The shortcoming of the method is that two methyl-etherified transformation efficiencys of the C-7 position of parent nucleus and C-10 position hydroxyl are very low, this is because C-7 position hydroxyl is easy to occur the epimerization reaction of anti-aldol condensation under highly basic effect, thus cause C-7 position hydroxy alkylated to be difficult to carry out, most yields very low (10% ~ 20%), and reaction system is complicated, be all adopt preparation liquid phase separation in prior art disclosed in RELATED APPLICATIONS, be unsuitable for industrialization and prepare XRP6258 on a large scale.
(2). cling to Ka Ting (10-DAB) for initiator to remove acetyl, first with pyridine solvent, the intermediate 6258-A preparing 7-OH and 13-OH and protected by triethyl silicon is simultaneously reacted with excessive chlorotriethyl silane (TESCl), then solvent and alkylating reagent is made with methyl iodide, take sodium hydride as alkali, complete 10-OH methyl-etherified product 6258-B, remove C-7 position and C-13 position silicon ether protecting group, solvent and alkylating reagent is made again with methyl iodide, take sodium hydride as alkali, complete 7-OH methyl-etherified product 6258-D, the last also deprotection that docks with side chain obtains XRP6258 (WO9630356):
The shortcoming of the method is that route is long, and the C-7 position hydroxyl methyl-etherified low conversion rate of parent nucleus, total recovery, lower than 10%, is unsuitable for industrialization and prepares XRP6258 on a large scale.
It is too low that above-mentioned two kinds of methods preparing XRP6258 have yield, and the defects such as purification difficult (multistep column chromatography), synthetic route are oversize, it limits industrial large-scale preparations and applicatio to a certain extent.
Summary of the invention
The object of this invention is to provide a kind of method preparing s-generation taxanes PTS Cabazitaxel newly, this synthetic method preparation efficiency is high, technique is simple, yield is high, cost is lower, easy handling, is suitable for large-scale manufacture and prepares s-generation taxanes PTS XRP6258.
The method preparing s-generation paclitaxel kind anti-cancer drugs Cabazitaxel of the present invention, by following reaction formula, synchronously Pummerer Rearrangement is carried out and Swern Oxidation reacts by methyl-sulphoxide/acetic anhydride, the C-7 of 10-deacetylation bar card fourth III (I) is obtained with high yield and regioselectivity, the two MTMization of C-10 position hydroxyl and C-13 position hydroxyl oxidize product II, then one kettle way completes C-13 position carbonyl and the C-7 of Compound II per, first sulphur methylene radical (MTM) the piptonychia sulfenyl operation of C-10 position obtains the parent nucleus IV of XRP6258, then carry out docking with various types of side chain, finally remove Side chain protective group and obtain products C abazitaxel (V).
Specifically, a kind of method preparing s-generation paclitaxel kind anti-cancer drugs Cabazitaxel of the present invention, it is characterized in that, it comprises step:
A. acetyl baccatin III (I is removed with 10-, 10-DAB) be initial reactant, synchronously carry out Pummerer to reset and Swern oxidizing reaction, C-7, C-10 position hydroxyl first sulphur methylene radical (MTM) obtaining I with high yield and regioselectivity is changed and C-13 hydroxyl oxidize product II;
B. one kettle way completes the parent nucleus IV that the C-13 position carbonyl of Compound II per and the operation of C-7, C-10 position first sulphur methylene radical (MTM) piptonychia sulfenyl obtain XRP6258;
C. docked with various types of side chain by the parent nucleus IV obtained, last deprotection base obtains product XRP6258 (V).
In the present invention, the Pummerer described in step a resets and reagent used in Swern oxidizing reaction is methyl-sulphoxide/acid anhydrides, and catalyzer used is various organic acid or mineral acid, and temperature of reaction is between 25 DEG C to 80 DEG C.
In embodiments of the invention, preferred catalyst is acetic acid or p-toluenesulphonic acids.
In the present invention, one kettle way described in step b completes the C-13 position carbonyl of Compound II per and the reagent of C-7, C-10 position first sulphur methylene radical (MTM) piptonychia sulfenyl operation use is Raney's nickel (Raney-nickel)/hydrogen etc., solvent used is selected from the group be made up of tetrahydrofuran (THF), ethanol, methyl alcohol and composition thereof, and temperature of reaction is between 25 DEG C to 60 DEG C;
In the present invention, the various side chains described in step c comprise: with beta-lactam, five yuan of oxazolidine carboxylic-acids, straight-chain carboxylic acid's classes etc. of different protecting group; The reagent that described deprotection base adopts is tetrabutyl ammonium fluoride (TBAF), hydrogen fluoride/pyridine, acetic acid/methyl alcohol, acetic acid/zinc etc.
In the present invention; described protecting group is the silicon ether protecting group that the alkyl or aryl such as t-Butyldimethylsilyl (TBS), triethyl silica-based (TES), triisopropylsilyl (TIPS), trimethyl silicon based (TMS) replaces, or methoxyl methyl (MOM), 1-ethoxyethyl group (EE).
The feature of the inventive method is:
Provide a gordian technique: synchronously carry out Pummerer Rearrangement by methyl-sulphoxide/acetic anhydride and Swern Oxidation reacts, obtain the two methylthiomethylene of C-7, C-10 position hydroxyl and the C-13 hydroxyl oxidize product II of 10-deacetylation bar card fourth III (I) with high regioselectivity;
Provide another gordian technique: the parent nucleus IV of the bis-alkylated XRP6258 of C-7 and C-10 position hydroxyl of preparation 10-deacetylation bar card fourth III (I);
Additionally provide gordian technique: carry out protecting group switching strategy at 7-OH, 10-OH, 13-OH respectively, be convenient to brief, cost is lower, synthesize XRP6258 with high yield.
Its full content see ProtectiveGroups in Organic Chemistry (4th edition.Publisher:Wiley-Interscience), can be incorporated herein at this by the kind of protecting group involved herein, the reagent going protecting group and method.It should be understood that, when have selected certain protecting group, those skilled in the art can select accordingly to the reagent and method going protecting group, and to this, it will not go into details.
Technical scheme of the present invention is described below in detail.
Concrete synthetic method:
Go acetyl baccatin III (I, 10-DAB) to set out by 10-, first two for its C-7, C-10 position hydroxyl methylthiomethylene and C-13 hydroxyl oxidize are prepared product II, concrete operation step is as follows:
Acetyl baccatin III (I is removed with 10-, 10-DAB) be initial reactant, solvent and reaction reagent is made with DMSO/ acetic anhydride/acetic acid, the two methylthiomethylene of C-7, C-10 hydroxyl and the C-13 hydroxyl oxidize product II of I is obtained with high yield and regioselectivity, for weak yellow foam shape solid, crude product, without the need to purifying, directly carries out next step piptonychia sulfenyl or C-13 position carbonyl reduction; Wherein the acid anhydrides of indication comprises diacetyl oxide, benzoyl oxide etc., and described catalyzer is various acid (such as acetic acid, p-toluenesulphonic acids etc.), and temperature of reaction is between 20 DEG C to 60 DEG C, and optimal reaction temperature is 25 DEG C.
Be dissolved in ethanol by intermediate II crude product, make catalyzer with Raney's nickel, carry out hydrogenolysis desulphurization reaction under room temperature, crude product obtains white powder parent nucleus IV sterling through simple recrystallization, and two step total recoverys are about 51%; Wherein, solvent used is the single or mixed solvents such as tetrahydrofuran (THF), ethanol, methyl alcohol, and temperature of reaction is between 25 DEG C to 60 DEG C.
Parent nucleus IV is carried out docking from C-3 position hydroxyl by the lactan (1.0eq to 2.0eq) that different protecting group is protected at-40 DEG C react; transformation efficiency with more than 90% obtains docking crude product IV-1; then remove pendant hydroxyl group protecting group, column chromatography purification obtains XRP6258 white foam solid.Wherein, docking reaction alkali used can be LiHMDS, NaHMDS, NaH etc., and solvent used is tetrahydrofuran (THF), dioxane etc.; Temperature of reaction used is between-60 DEG C to 25 DEG C, and beta-lactam intermediate equivalents used is 1.0 to 2.0 equivalents (relative to female ring intermediate compound IV).The silicon ether protective group R of described beta-lactam C-3 position 1for the silicon ether protecting group etc. that TBS, TES, TIPS, TMS or aryl replace, now protecting group removes reagent is TBAF, and solvent is tetrahydrofuran (THF); When beta-lactam C-3 position hydroxyl protecting group is the protecting groups such as MOM, EE, it is acetic acid/methyl alcohol etc. that protecting group now removes reagent.
Parent nucleus IV and C-2, C-3 position functional group are carried out condensation by five yuan of oxazolidine carboxylic acids (1.1eq to 2.0eq) that different protecting group is protected under room temperature, transformation efficiency with more than 90% obtains docking crude product IV-2, then remove Side chain protective group, column chromatography purification obtains XRP6258 white foam solid; Wherein, R 3, R 4represent different alkyl, aryl etc.; docking reaction reagent used is conventional condensing agent: N; N '-dicyclohexylcarbodiimide (DCC), 1-(3-DimethylAminopropyl)-3-ethyl carbodiimide (EDC) etc.; solvent used is tetrahydrofuran (THF), methylene dichloride, chloroform etc., and it is zinc powder/acetic acid etc. that protecting group now removes reagent.
The straight-chain carboxylic acid (1.0-2.0eq) that parent nucleus IV and C-2, C-3 position functional group are protected by different protecting group is carried out condensation under room temperature; transformation efficiency with more than 90% obtains docking crude product IV-3; then remove Side chain protective group, column chromatography purification obtains XRP6258 white foam solid.Temperature of reaction used is between 0 DEG C to 25 DEG C, and side chain intermediate used is 1.0 to 2.0 equivalents (relative to female ring intermediate compound IV).The blocking group R of described C-2 position 2for the silicon ether protecting group etc. that TBS, TES, TIPS, TMS, aryl replace, now protecting group removes reagent is TBAF, and solvent is tetrahydrofuran (THF); The blocking group R of described C-2 position 2for MOM), the protecting group such as EE time, it is acetic acid/methyl alcohol etc. that protecting group now removes reagent.
Compared with prior art, semisynthesis of the present invention has the advantage such as preparation process easy (, without the need to purification process, purge process is simple for moiety intermediate), yield is high, cost is lower, easy handling, is suitable for large-scale manufacture XRP6258.
Embodiment
The reagent such as acetic anhydride, acetic acid, methyl alcohol and ethanol that the present invention is used are commercial reagent and directly use, tetrahydrofuran (THF) (THF) with front with sodium silk backflow heavily steam, methyl-sulphoxide (DMSO) with molecular sieve drying.10-goes acetyl bar Ka Ting (10-DAB) to be buied by Hao Xuan bio tech ltd, Xi'an.Sherwood oil used is 60 ~ 90 DEG C of boiling ranges, and without specified otherwise, other is common domestic analytical reagent.With thin-layer chromatography (TLC) detection reaction process, thin layer plate used is that Yantai chemical industry institute produces thin-layer chromatography silica gel precoated plate (silica gel granularity 10 ~ 40m).Ultraviolet detection wavelength is 254nm; With 5% aubepine-5% vitriol oil-1% Glacial acetic acid-ethanolic soln heating colour developing.Column chromatography used silica gel is purchased from subsidiary factory of Haiyang Chemical Plant, Qingdao, and specification is 100 ~ 200 orders, 200 ~ 300 and 300 ~ 400 orders; Nuclear magnetic resonance spectrometer (JEOL-ECP-400, interior mark: TMS, DSS), Fourier transformation infrared spectrometer (Nicolet Nexus-470), mass spectrograph (Q-TOF Global).
Embodiment 1
Prepare Compound II per
By 10-DAB (I) (27.3g, 50.0mmol) be dissolved in dry DMSO (200mL), add acetic anhydride (200mL), argon shield, stirred overnight at room temperature, after thin-layer chromatography detection reaction, by reaction solution concentrating under reduced pressure evaporate to dryness, residue obtained ethyl acetate (1.5L) is diluted, use saturated sodium bicarbonate solution (300mL × 6) successively, distilled water (200mL × 3), saturated sodium-chloride water solution (200mL × 3) washs, anhydrous sodium sulfate drying, concentrate and obtain weak yellow foam shape solid product II (30.2g, yield about 91.8%), not purified directly carry out next step reaction, 1h-NMR (400MHz, CDCl 3): δ 8.06 (d, 2H, J=7.0Hz, Ph-H), 7.62 (t, 1H, J=7.6Hz, Ph-H), 7.49 (t, 2H, J=7.6Hz, Ph-H), 5.80 (s, 1H, H-10), 5.67 (d, 1H, J=6.7Hz, H-2), 4.94 (d, 1H, J=9.2Hz, H-5), 4.84 (d, 1H, J=11.6Hz, CH 3sC hhO), 4.73 (d, 1H, J=11.6Hz, CH 3sCH ho), 4.69 (d, 1H, J=11.9Hz, CH 3sC hhO), 4.59 (d, 1H, J=11.9Hz, CH 3sCH ho), 4.33 (d, 1H, J=8.3Hz, H-20a), 4.28 (dd, 1H, J=10.4,6.7Hz, H-7), 4.12 (d, 1H, J=8.8Hz, H-20b), 3.95 (d, 1H, J=6.7Hz, H-3), 2.93 (d, 1H, J=19.9Hz, H-14a), 2.82-2.76 (m, 1H, H-6a), 2.66 (d, 1H, J=19.6Hz, H-14b), 2.21 (s, 6H, C h 3sCH 2o in C-7and C-10), 2.20 (s, 3H, C h 3cO), 2.17 (s, 3H, C h 3in C-18), 1.85-1.79 (m, 1H, H-6b), 1.71 (s, 3H, C h 3in C-19), 1.26 (s, 3H, C h 3), 1.21 (s, 3H, C h 3),
ESI-MS(m/z)：663.3[M+H] +(Calcd 662.2)、685.2[M+Na] +、701.2[M+K] +.
Preparation compound IV
By II (6.6g, 10.0mmol) be dissolved in the ethanol (150mL) of 95%, add Raney's nickel (about 8g), under 3 normal atmosphere hydrogen, 50 DEG C are stirred 20h, after thin-layer chromatography detection reaction, by reaction solution suction filtration, with a large amount of ethyl acetate drip washing filter cakes, filtrate, with ethyl acetate (500mL) dilution, is washed with saturated sodium-chloride water solution (150mL × 3), anhydrous sodium sulfate drying, concentrated, crude product recrystallization from ethyl acetate/petroleum ether obtains white powdery solids product IV (3.4g, yield: 58.1%); 1h-NMR (400MHz, DMSO-d 6): δ 7.99 (d, 2H, J=7.4Hz, Ph-H), 7.64 (t, 1H, J=7.4Hz, Ph-H), 7.54 (t, 2H, J=7.4Hz, Ph-H), 5.35 (d, 1H, J=7.1Hz, H-2), 5.30 (d, 1H, J=4.7Hz, O h-13), 4.95 (d, 1H, J=9.0Hz, H-5), 4.72 (s, 1H, H-10), 4.69-4.63 (m, 1H, H-13), 4.38 (s, O h-1), 4.03 (d, 1H, J=8.2Hz, H-20a), 3.99 (d, 1H, J=8.2Hz, H-20b), 3.79 (dd, 1H, J=9.8,6.3Hz, H-7), 3.73 (d, 1H, J=7.0Hz, H-3), 3.27 (s, 3H, OC h 3), 3.20 (s, 3H, OC h 3), 2.71-2.60 (m, 1H, H-6a), 2.18 (s, 3H, C h 3cO), 2.16-2.13 (m, 2H, H-14), 1.95 (s, 3H, C h 3in C-18), 1.49 (s, 3H, C h 3in C-19), 1.53-1.43 (m, 1H, H-6b), 1.20 (s, 3H, C h 3), 0.91 (s, 3H, C h 3);
ESI-MS(m/z)：573.3[M+H] +(Calcd 572.3).
Preparation compound IV-1-1
By IV (1.43g; 2.5mmol) with X-6 (1.2g; 3.3mmol) be dissolved in dry THF (300mL); argon shield, is cooled to-50 DEG C, drips the THF solution (4.0mL of the LiHMDS of 1M; 4.0mmol); after continuing reaction 2h, TLC detection reaction at-50 DEG C, add saturated NH 4the Cl aqueous solution (50mL) termination reaction, reaction solution EtOAc (200mL) dilutes, be separated organic phase, aqueous phase EtOAc (100mL × 3) extracts, merge organic phase, use saturated sodium bicarbonate solution (100mL × 3), the saturated NaCl aqueous solution (50mL × 3) to wash successively, anhydrous sodium sulfate drying, concentrated obtain white solid crude product IV-1-1 (2.7g), not purifiedly directly carry out next step reaction; 1h NMR (400MHz, CDCl 3) δ 8.11 (d, J=7.3Hz, 2H, Ph-H), 7.56 (t, J=7.6Hz, 1H, Ph-H), 7.48 (t, J=7.6Hz, 2H, Ph-H), 7.37 (t, J=7.3Hz, 2H, Ph-H), 7.31-7.26 (m, 3H, Ph-H), 6.29 (broad t, J=8.9Hz, 1H, H-13), 5.66 (d, J=7.0Hz, 1H, H-2), 5.48 (broad d, J=9.0Hz, 1H, CON h), 5.30 (broad d, 1H, H-3 '), 5.00 (d, J=8.9Hz, 1H, H-5), 4.81 (s, 1H, H-10), 4.55 (s, 1H, H-2 '), 4.32 (d, J=8.6Hz, 1H, H-20a), 4.19 (d, J=8.3Hz, 1H, H-20b), 3.90 (dd, J=10.4,6.4Hz, 1H, H-7), 3.87 (d, J=7.3Hz, 1H, H-3), 3.46 (s, 3H, OC h 3), 3.31 (s, 3H, OC h 3), 2.75-2.69 (m, 1H), 2.52 (s, 3H, C h 3cO in C-4), 2.38-2.32 (m, 1H), 2.21-1.95 (m, 1H), 2.17 (s, 3H), 1.95 (s, 3H), 1.87-1.75 (m, 1H), 1.72 (s, 3H), 1.33 (s, 9H me 3cand C h 3 ), 1.24 (s, 3H, C h 3 ), 1.20 (s, 3H, C h 3 ), 0.79 (t, J=7.9Hz, 9H), 0.48-0.30 (m, 6H).
Preparation compound IV-1-2
By IV (1.43g; 2.5mmol) with Y-6 (1.1g; 3.3mmol) be dissolved in dry THF (300mL); argon shield, is cooled to-50 DEG C, drips the THF solution (4.0mL of the LiHMDS of 1M; 4.0mmol); after continuing reaction 2h, TLC detection reaction at-50 DEG C, add saturated NH 4the Cl aqueous solution (50mL) termination reaction, reaction solution EtOAc (200mL) dilutes, be separated organic phase, aqueous phase EtOAc (100mL × 3) extracts, merge organic phase, use saturated sodium bicarbonate solution (100mL × 3), the saturated NaCl aqueous solution (50mL × 3) to wash successively, anhydrous sodium sulfate drying, concentrated obtain white solid crude product VII-1-2 (2.5g), not purifiedly directly carry out next step reaction;
Prepare compound V
Crude product IV-1-1 (2.7g) is dissolved in THF (100mL), TBAF is added under ice bath, continue reaction 2h, after TLC detection reaction, reaction solution is concentrated evaporate to dryness, gains EtOAc (200mL) is dissolved, distilled water (100mL × 3), the saturated NaCl aqueous solution (100mL × 3) is used to wash successively, anhydrous sodium sulfate drying, concentrated, through column chromatography (ethyl acetate/petroleum ether=1: 3) obtain white foam solid Cabazitaxel (XRP6258, V), (1.9g, two step total recoverys: 90.1%); 1hNMR (400MHz, CDCl 3) δ 8.08 (d, J=7.7Hz, 2H, Ph-H), 7.60 (t, J=7.3Hz, 1H, Ph-H), 7.48 (t, J=7.7Hz, 2H, Ph-H), 7.42-7.30 (m, 5H, Ph-H), 6.20 (broad t, J=8.4Hz, 1H, H-13), 5.62 (d, J=7.0Hz, 1H, H-2), 5.43 (broad d, J=9.5Hz, 1H, CON h), 5.29 (s, 1H, H-10), 5.26 (broad d, J=8.4Hz, 1H, H-3 '), 4.96 (d, J=8.8Hz, 1H, H-5), 4.79 (s, 1H, H-2 '), 4.29 (d, J=8.4Hz, 1H, H-20a), 4.16 (d, J=8.4Hz, 1H, H-20b), 4.79 (broad s, 1H), 3.85 (dd, J=10.3,6.6Hz, 1H, H-7), 3.80 (d, J=7.0Hz, 1H, H-3), 3.44 (s, 3H, OC h 3), 3.29 (s, 3H, OC h 3), 2.73-2.65 (m, 1H, H-6b), 2.35 (s, 3H, C h 3cO in C-4), 2.29-2.24 (m, 2H, H-14), 1.87 (s, 3H, C h 3 ), 1.82-1.74 (m, 1H, H-6a), 1.71 (s, 3H, C h 3 ), 1.66 (s, 1H, 1-O h), 1.61 (s, 3H, C h 3 ), 1.35 (s, 9H, me 3c and C h 3), 1.21 (s, 3H, C h 3 ), 1.20 (s, 3H, C h 3 );
ESI-MS(m/z)：836.3[M+H] +(Calcd 835.4)、858.3[M+Na] +、875.2[M+K] +.
Prepare compound V
Crude product IV-1-2 (2.5g) is dissolved in THF (100mL), add under ice bath HOAc/MeOH (1: 1) (50mL), 2h is reacted at 50 DEG C, after TLC detection reaction, reaction solution is concentrated, gains EtOAc (200mL) is dissolved, use saturated sodium bicarbonate solution (100mL × 6) successively, the saturated NaCl aqueous solution (100mL × 3) washing, anhydrous sodium sulfate drying, concentrated, through column chromatography (ethyl acetate/petroleum ether=1: 3) obtain white foam solid Cabazitaxel (XRP6258, V), (2.1g, two step total recoverys: 94.2%).

Claims (1)

1. prepare a method of s-generation paclitaxel kind anti-cancer drugs Cabazitaxel, described Cabazitaxel has the structure of formula (V), it is characterized in that, described method comprises step:
A. go acetyl Bakating III for initial reactant with 10-, described 10-goes acetyl Bakating III to have the structure of formula I, synchronously carry out Pummerer to reset and Swern oxidizing reaction, obtain C-7, C-10 position hydroxyl first sulphur methylenation and the C-13 hydroxyl oxidize product II of I with high yield and regioselectivity;
B. one kettle way completes the parent nucleus IV that the C-13 position carbonyl of compound ii and the operation of C-7, C-10 position first sulphur methylene radical piptonychia sulfenyl obtain Cabazitaxel;
C. docked with various types of side chain by the parent nucleus IV obtained, last deprotection base obtains product (V);
The Pummerer of described step a resets and reagent used in Swern oxidizing reaction is methyl-sulphoxide/acid anhydrides, and used catalyst is acetic acid or p-toluenesulphonic acids, and temperature of reaction is between 25 DEG C to 80 DEG C;
The one kettle way of described step b completes the C-13 position carbonyl of compound ii and the reagent of C-7, C-10 position first sulphur methylene radical piptonychia sulfenyl operation use is Raney's nickel/hydrogen, solvent used is selected from the group be made up of tetrahydrofuran (THF), ethanol, methyl alcohol and composition thereof, and temperature of reaction is between 25 DEG C to 60 DEG C;
The various side chains of described step c comprise: with the beta-lactam of different protecting group, five yuan of oxazolidine carboxylic-acids or straight-chain carboxylic acid's class;
The silicon ether protecting group that described protecting group is selected from that t-Butyldimethylsilyl, triethyl are silica-based, triisopropylsilyl or trimethyl silicon based alkyl or aryl replace, or methoxyl methyl or 1-ethoxyethyl group;
The reagent that the deprotection base of described step c adopts is selected from tetrabutyl ammonium fluoride, hydrogen fluoride/pyridine, acetic acid/methyl alcohol or acetic acid/zinc.
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CN100417649C (en) * 2006-04-05 2008-09-10 云南思摩贝特生物科技有限公司 Preparation method of doxytasai
CN102060815A (en) * 2010-12-24 2011-05-18 重庆泰濠制药有限公司 Preparation method of taxanes compound
EP2330100A1 (en) * 2009-11-04 2011-06-08 Emcure Pharmaceuticals Limited An improved process for preparation of taxane derivatives

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EP2330100A1 (en) * 2009-11-04 2011-06-08 Emcure Pharmaceuticals Limited An improved process for preparation of taxane derivatives
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