CN103012329A - Preparation method of taxol anticancer drugs Cabazitaxel XRP6258 - Google Patents
Preparation method of taxol anticancer drugs Cabazitaxel XRP6258 Download PDFInfo
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- CN103012329A CN103012329A CN2011102870829A CN201110287082A CN103012329A CN 103012329 A CN103012329 A CN 103012329A CN 2011102870829 A CN2011102870829 A CN 2011102870829A CN 201110287082 A CN201110287082 A CN 201110287082A CN 103012329 A CN103012329 A CN 103012329A
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- xrp6258
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N OC(c1ccccc1)=O Chemical compound OC(c1ccccc1)=O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 7
- 0 CC(CC1(*)C2)([C@@]1(C)C([C@]1*)=C(*)C2=O)C(C)(C)C1=O Chemical compound CC(CC1(*)C2)([C@@]1(C)C([C@]1*)=C(*)C2=O)C(C)(C)C1=O 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N OC(CCc1ccccc1)=O Chemical compound OC(CCc1ccccc1)=O XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-M [O-]C(CCc1ccccc1)=O Chemical compound [O-]C(CCc1ccccc1)=O XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
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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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to the field of drug synthesis, and relates to a method for synthesizing a second-generation taxol anticancer drugs Cabazitaxel XRP6258. The method comprises the following steps of: obtaining C-7 and C-10 bit hydroxy methyl mercaptan methylene (MTM) and C-13 bit oxhydryl oxydic key intermediate (II) of 10-oxhydryl baccatin III(I) by high regioselectivity, reducing C-13 bit carbonyl to obtain a mother nucleus midbody (III), carrying out butt joint with various types of side chains to obtain butt joint product midbodies (IV-1) and (IV-2), and removing a side-chain protecting group after the di-methylthio is removed or removing the di-methylthio of the nuclear parent after the side-chain protecting group is removed to obtain a product Cabazitaxel XRP6258 (V). The method disclosed by the invention has the advantages of being simple in preparation process, high in yield, lower in cost, easy to operate and the like, so that the XRP6258 can be produced and prepared on a large scale.
Description
Technical field
The invention belongs to the synthetic field of medicine; the method that relates to synthetic s-generation paclitaxel kind anti-cancer drugs Cabazitaxel XRP6258; be specifically related to; a kind of novel method of synthetic XRP6258 (V) take 10-deacetylation bar card fourth III (I) as starting raw material; described method has preparation process efficient height, the advantages such as technique is simple, yield is high, cost is lower, easy handling, is suitable for large-scale manufacture XRP6258.
Background technology
Taxol (Paclitaxel) and semi-synthetic analogue Docetaxel (Docetaxel) thereof are the star molecules of world today's antitumor drug, it is mainly used in treating ovarian cancer, the esophageal carcinoma, urinary tract transfer epithelial cancer, incidence squama cancer, mammary cancer, nonsmall-cell lung cancer, pernicious black solid tumor and some other solid tumors clinically, evident in efficacy to treatment Metastatic carcinoma in the ovary, mammary cancer especially, be acknowledged as very rising PTS.Yet taxol is the same with other chemotherapeutics, and it is for multidrug resistance (MDR) tumour non-activity almost, thereby exploitation still keeps the taxanes cancer therapy drug of curative effect extremely urgent for multidrug resistance of tumor.
Described Cabazitaxel (XRP6258) is the bearing taxanes by the research and development of French Sanofi-Aventis corporate investment, and its constructional feature is that the C-7 of docetaxel, the two methyl-etherifieds of C-10 position hydroxyl are modified.Cabazitaxel is the weak effect substrate of P-glycoprotein, thereby than taxol and the easier hemato encephalic barrier (BBB) that passes through of docetaxel.In June, 2010, Cabazitaxel preferentially examines the approval listing because its curative effect brilliance obtains FDA by III phase clinical study smoothly, as the medicine for the treatment of late period, hormone antagonist type prostate cancer first-selectedly, also be used for the advanced prostate cancer patient of even aggravation invalid to docetaxel.Clinical studies show XRP6258 medication can obviously prolong the survival time of tumour patient, brings the patient more treatment machine meeting.Have research once to use the patient of Docetaxel to carry out the safety and efficacy clinical study of XRP6258 to 755, the result shows that mean survival time reaches 15.1 months, has significantly prolonged patient's survival time.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). to go acetyl bar Ka Ting (10-DAB) as initiator, take methyl iodide or methyl sulfate as alkylating reagent, take reagent such as sodium hydride, potassium hydride KH, n-Butyl Lithium, LiHMDS, NaHMDS as alkali, a step is finished C-7 position and the two methyl-etherifieds (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 the highly basic effect, thereby cause C-7 position hydroxy alkylated to be difficult to carry out, most yields very low (10%～20%), and reaction system is complicated, all be to adopt the preparation liquid phase separation in the patent, be unsuitable for large-scale industrialization ground preparation XRP6258.
(2). to go acetyl bar Ka Ting (10-DAB) as initiator; first with pyridine solvent; the intermediate 6258-A that is protected by triethyl silicon with excessive chlorotriethyl silane (TESCl) reaction preparation 7-OH and 13-OH while; then make solvent and alkylating reagent with methyl iodide; take sodium hydride as alkali; finish 10-OH methyl-etherified product 6258-B; remove C-7 position and C-13 position silicon ether protecting group; make solvent and alkylating reagent with methyl iodide again; take sodium hydride as alkali; finish 7-OH methyl-etherified product 6258-D, dock at last also deprotection obtains XRP6258 (WO9630356) with side chain:
The shortcoming of the method is that route is long, and the C-7 position hydroxyl methyl-etherified low conversion rate of parent nucleus, and total recovery is lower than 10%, is unsuitable for the preparation XRP6258 of large-scale industrialization.
Above-mentioned two kinds of methods that prepare XRP6258 exist yield too low, and the defective such as purification difficult (multistep column chromatography), synthetic route are oversize has limited industrial large-scale preparation and application to a certain extent.
Summary of the invention
The purpose of this invention is to provide a kind of method for preparing paclitaxel kind anti-cancer drugs Cabazitaxel XRP6258, present method efficient 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 for preparing paclitaxel kind anti-cancer drugs Cabazitaxel XRP6258 of the present invention, by following reaction formula, the C-7 and the C-10 position hydroxyl first sulphur methylene radical (MTM) that obtain 10-deacetylation baccatin III (I) with high regioselectivity are changed the simultaneously key intermediate (II) of C-13 position hydroxyl oxidize, then its C-13 position carbonyl reduction is obtained parent nucleus intermediate (III), dock with various types of side chains again and obtain docking product intermediate (IV-1) and (IV-2), then remove first remove Side chain protective group or remove first its Side chain protective group behind its pair methylthio group after, remove two methylthio groups of parent nucleus, obtain products C abazitaxel XRP6258 (V);
Particularly, the method for preparing paclitaxel kind anti-cancer drugs Cabazitaxel XRP6258 of the present invention may further comprise the steps:
A. remove acetyl baccatin III (I with 10-, 10-DAB) be initial reactant, carry out synchronously Pummerer and reset and the Swern oxidizing reaction, the C-7, the C-10 position hydroxyl first sulphur methylene radical (MTM) that obtain I with high yield and regioselectivity are changed and C-13 hydroxyl oxidize product II;
B. intermediate II is obtained intermediate III through C-13 position carbonyl reduction;
C. the intermediate III that obtains is docked with various types of side chains and obtain docking product intermediate (IV-1) and (IV-2); its pair methylthio group that then removes first obtain respectively (V-1) and (V-2) after; remove Side chain protective group; obtain Cabazitaxel XRP6258 (V), perhaps remove first two methylthio groups that its Side chain protective group obtains removing after (V-3) parent nucleus and obtain products C abazitaxel XRP6258 (V).
Among the present invention, reagent used in the Pummerer rearrangement described in the step a and the Swern oxidizing reaction is methyl-sulphoxide/acid anhydrides, and used catalyzer is various organic acids or mineral acid, and temperature of reaction is between 25 ℃ to 80 ℃.
In the embodiments of the invention, catalyst system therefor is acetic acid or p-toluenesulphonic acids.
Among the present invention, the reagent that the C-13 position carbonyl reduction described in the step b adopts is sodium borohydride, and temperature of reaction is between-10 ℃ to 25 ℃.
Among the present invention, the various side chains described in the step c comprise: with the beta-lactam of different protecting groups, five yuan of oxazolidine carboxylic-acids, straight-chain carboxylic acid's class etc.; The reagent that described deprotection base adopts is tetrabutyl ammonium fluoride (TBAF), hydrogen fluoride/pyridine, acetic acid/methyl alcohol, acetic acid/zinc etc.; The reagent that described piptonychia sulfenyl uses is Raney's nickel (Raney-nickel)/hydrogen etc., and used solvent is selected from the group that is comprised of tetrahydrofuran (THF), ethanol, methyl alcohol and composition thereof, and temperature of reaction is between 25 ℃ to 60 ℃.
Among the present invention; described protecting group is the silicon ether protecting group that the alkyl or aryls such as t-Butyldimethylsilyl (TBS), triethyl silica-based (TES), triisopropylsilyl (TIPS), trimethyl silicon based (TMS) replace, perhaps methoxyl methyl (MOM), 1-ethoxyethyl group (EE).
The characteristics of the method for the invention are:
Provide a gordian technique: carry out synchronously Pummerer Rearrangement and Swern Oxidation reaction by methyl-sulphoxide/acetic anhydride, obtain the two methylthio group methylenations 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;
Another gordian technique also is provided: carry out the protecting group switching strategy at 7-OH, 10-OH, 13-OH respectively, be convenient to brief, cost is lower, synthetic XRP6258 with high yield.
The kind of related protecting group, the reagent that goes protecting group and method can referring to Protective Groups in Organic Chemistry (4th edition.Publisher:Wiley-Interscience), be incorporated herein its full content at this among the present invention.It should be understood that when having selected certain protecting group, those skilled in the art can select accordingly to reagent and the method for going protecting group, it will not go into details to this.
The below will describe technical scheme of the present invention in detail.
Concrete synthetic method:
Go acetyl baccatin III (I, 10-DAB) to set out by 10-, first its C-7, the two methylthio group methylenations of C-10 position hydroxyl and C-13 hydroxyl oxidize are prepared product II, concrete operation step is as follows:
Remove acetyl baccatin III (I with 10-, 10-DAB) be initial reactant, make solvent and reaction reagent with DMSO/ acetic anhydride/acetic acid, obtain the two methylthio group methylenations of C-7, C-10 hydroxyl and the C-13 hydroxyl oxidize product II of I with high yield and regioselectivity, be weak yellow foam shape solid, crude product need not 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 acidss etc.), and temperature of reaction is between 20 ℃ to 60 ℃, and optimal reaction temperature is 25 ℃.
Intermediate II and sodium borohydride (5.0eq to 10.0eq) are reacted under ice bath, obtain the intermediate III that C-13 position carbonyl is reduced with high regioselectivity and stereoselectivity, yield is almost quantitative; Crude product need not purifying, directly carries out next step piptonychia sulfenyl reaction; Wherein, the original reagent of going back of described C-13 position carbonyl is sodium borohydride, and described solvent is tetrahydrofuran (THF)/methyl alcohol etc., and described temperature of reaction is between-10 ℃ to 25 ℃.
Parent nucleus III is docked reaction from the lactan (1.0eq to 2.0eq) that C-3 position hydroxyl is protected by different protecting groups under-40 ℃, obtain docking crude product IV-1 with the transformation efficiency more than 90%, wherein the used alkali of docking reaction can be LiHMDS, NaHMDS, NaH etc., and used solvent is tetrahydrofuran (THF), dioxane etc.; Used temperature of reaction is between-60 ℃ to 25 ℃, and used beta-lactam intermediate equivalents is 1.0 to 2.0 equivalents (with respect to the female ring intermediate III); Crude product IV-1 is dissolved in the ethanol, makes catalyzer with Raney's nickel, carry out the hydrogenolysis desulphurization reaction under the room temperature and obtain the V-1 crude product, the solvent that reacts used is the single or mixed solvents such as tetrahydrofuran (THF), ethanol, methyl alcohol, and temperature of reaction is between 25 ℃ to 60 ℃; The V-1 crude product is removed the pendant hydroxyl group protecting group can obtain products C abazitaxel; The silicon ether protective group R of described beta-lactam C-3 position
1The silicon ether protecting group that replaces for TBS, TES, TIPS, TMS or aryl etc., this moment protecting group to remove reagent be TBAF, solvent is tetrahydrofuran (THF); When beta-lactam C-3 position hydroxyl protecting group was the protecting group such as MOM, EE, it was acetic acid/methyl alcohol etc. that the protecting group of this moment removes reagent.
Parent nucleus III is carried out condensation from five yuan of oxazolidine carboxylic acids (1.1eq to 2.0eq) that C-2, C-3 position functional group are protected by different protecting groups under room temperature, obtain IV-2 docking crude product with the transformation efficiency more than 90%, then remove two methylthio groups and the Side chain protective group of crude product, column chromatography purification obtains XRP6258 white foam shape solid (working method as mentioned above); Wherein, R
2, R
3Represent different alkyl, aryl etc.; the used reagent of docking reaction is condensing agent commonly used: N; N '-dicyclohexylcarbodiimide (DCC), 1-(3-dimethyl amine propyl group)-3-ethyl carbodiimide (EDC) etc.; used solvent is tetrahydrofuran (THF), methylene dichloride, chloroform etc., and it is zinc powder/acetic acid etc. that the protecting group of this moment removes reagent.
Parent nucleus III is carried out condensation from the straight-chain carboxylic acid (1.0-2.0eq) that the C-2 hydroxyl is protected by different protecting groups under room temperature; obtain docking crude product IV-1 with the transformation efficiency more than 90%; then remove Side chain protective group, column chromatography purification obtains XRP6258 white foam shape solid.Used temperature of reaction is between 0 ℃ to 25 ℃, and used side chain intermediate is 1.0 to 2.0 equivalents (with respect to the female ring intermediate III); The blocking group R of described C-2 position
1The silicon ether protecting group that replaces for TBS, TES, TIPS, TMS, aryl etc., this moment protecting group to remove reagent be TBAF, solvent is tetrahydrofuran (THF); The blocking group R of described C-2 position
1Be MOM), during the protecting group such as EE, it is acetic acid/methyl alcohol etc. that the protecting group of this moment removes reagent.
Docking crude product IV-1 and IV-2 also can remove successively Side chain protective group and obtain the V-2 crude product, then take off two methylthio groups and obtain XRP6258 sterling (working method is the same).
Compared with prior art, the advantages such as semisynthesis of the present invention has preparation process easy (the part intermediate need not purification process, and purge process is simple), yield is high, cost is lower, easy handling are suitable for large-scale manufacture XRP6258.
Embodiment
The reagent such as used acetic anhydride, acetic acid, methyl alcohol and ethanol are the commercial reagent and directly use, and tetrahydrofuran (THF) (THF) heavily steams with front the backflow with the sodium silk, methyl-sulphoxide (DMSO) with
Molecular sieve drying.10-goes acetyl bar Ka Ting (10-DAB) to be buied by Xi'an sky pavilion bio tech ltd.Used sherwood oil is 60～90 ℃ of boiling ranges, and without specified otherwise, other is common domestic analytical reagent.With thin-layer chromatography (TLC) detection reaction process, used thin layer plate is that Yantai chemical industry institute produces thin-layer chromatography silica gel precoated plate (silica gel granularity 10～40m).The ultraviolet detection wavelength is 254nm; With 5% aubepine-5% vitriol oil-1% Glacial acetic acid-ethanolic soln heating colour developing.The column chromatography used silica gel is available 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
1. prepare Compound I I
With 10-DAB (I) (27.3g, 50.0mmol) be dissolved among the dry DMSO (200mL), add acetic anhydride (200mL), argon shield, stirred overnight at room temperature, after the thin-layer chromatography detection reaction is complete, with reaction solution concentrating under reduced pressure evaporate to dryness, dilute with ethyl acetate (1.5L) residue obtained, use successively saturated sodium bicarbonate solution (300mL * 6), distilled water (200mL * 3), saturated sodium-chloride water solution (200mL * 3) washing, anhydrous sodium sulfate drying, the concentrated weak yellow foam shape solid product II (28.1g that obtains, yield about 85.1%), not purifiedly 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-7 and 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]
+.
2. preparation compound III
With II (6.6g; 10.0mmol) be dissolved in dry tetrahydrofuran (THF)/methyl alcohol (200mL); argon shield; slowly drip sodium borohydride (7.4g under the ice bath; 200.0mmol) tetrahydrofuran solution (200mL); be controlled in the 1h and dropwise; continue to stir 4h; after the thin-layer chromatography detection reaction is complete; with reaction solution saturated ammonium chloride solution (300mL) termination reaction; mixed solution separates organic phase with ethyl acetate (300mL) dilution, and water is with using successively ethyl acetate (100mL * 3) extraction; merge organic phase; use successively 1M hydrochloric acid (100mL * 3); saturated sodium bicarbonate aqueous solution (100mL * 3); saturated sodium-chloride water solution (100mL * 3) washing, anhydrous sodium sulfate drying, concentrated.Crude product is through column chromatography (EtOAc/Ligroin=5: 1) obtain white foam shape solid product IV (6.5g, yield: 96.0%);
1H-NMR (400MHz, CDCl
3): δ 8.10 (d, 2H, J=8.2Hz, Ph-H), 7.60 (t, 1H, J=7.0Hz, Ph-H), 7.48 (t, 2H, J=7.4Hz, Ph-H), 5.80 (m, 2H, H-10 and H-2), 4.99 (d, 1H, J=9.4Hz, H-5), 4.88 (t, 1H, J=7.8Hz, H-13), 4.74 (m, 2H, CH
3SC
H 2O), 4.68 (d, 1H, J=11.7Hz, CH
3SC
HHO), 4.61 (d, 1H, J=11.7Hz, CH
3SCH
HO), 4.33-4.27 (m, 2H, J=8.3Hz, H-20a and H-7), 4.16 (d, 1H, J=8.2Hz, H-20b), 3.94 (d, 1H, J=6.7Hz, H-3), 2.81-2.78 (m, 2H, H-6a and H-14a), 2.29 (s, 3H, C
H 3CO), 2.21-2.17 (m, 9H), 1.87-1.81 (m, 2H, H-6b and H-14a), 1.73 (s, 3H, C
H 3In C-19), 1.18 (s, 3H, C
H 3), 1.06 (s, 3H, C
H 3);
3. prepare compound vi I
With III (1.6g; 2.5mmol) and X-6 (1.2g; 3.3mmol) be dissolved among the dry THF (100mL); argon shield is cooled to-50 ℃, drips the THF solution (4.0mL of the LiHMDS of 1M; 4.0mmol);-50 ℃ of lower reaction 2h that continue after the TLC detection reaction is complete, add saturated NH
4The Cl aqueous solution (50mL) termination reaction, reaction solution dilutes with EtOAc (200mL), separate organic phase, water extracts with EtOAc (100mL * 3), merge organic phase, use successively saturated sodium bicarbonate solution (100mL * 3), the saturated NaCl aqueous solution (50mL * 3) washing, anhydrous sodium sulfate drying, the concentrated about 3.1g of white solid crude product IV-1-1 that obtains not purifiedly directly carries out next step reaction.
4. prepare compound V-1
IV-1-1 (3.1g) is dissolved in 95% the ethanol (150mL), add Raneynickel (about 5 grams), under 3 normal atmosphere hydrogen, 50 ℃ are stirred 12h, after the thin-layer chromatography detection reaction is complete, with the reaction solution suction filtration, with a large amount of ethyl acetate drip washing filter cakes, filtrate is concentrated, and enriched material dilutes with ethyl acetate (500mL), wash with saturated sodium-chloride water solution (150mL * 3), anhydrous sodium sulfate drying, concentrated, obtain white foam shape solid (V-1 through column chromatography (ethyl acetate/petroleum ether=1: 5), 1.7g, two step total recoverys: 73.8%).
5. prepare compound V
Crude product V-1 (2.8g) is dissolved among the THF (100mL), add TBAF under the ice bath, continue reaction 2h, after the TLC detection reaction is complete, with the concentrated evaporate to dryness of reaction solution, gains are dissolved with EtOAc (200mL), use successively distilled water (100mL * 3), the saturated NaCl aqueous solution (100mL * 3) washing, anhydrous sodium sulfate drying, concentrated, obtain white foam shape solid Cabazitaxel (XRP6258, V) through column chromatography (ethyl acetate/petroleum ether=1: 3), (1.9g, two step total recoverys: 90.1%);
1H NMR (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]
+.
6. prepare compound IV-1-2
With III (1.6g; 2.5mmol) and Y-6 (1.1g; 3.3mmol) be dissolved among the dry THF (100mL); argon shield is cooled to-50 ℃, drips the THF solution (4.0mL of the LiHMDS of 1M; 4.0mmol);-50 ℃ of lower reaction 2h that continue after the TLC detection reaction is complete, add saturated NH
4The Cl aqueous solution (50mL) termination reaction, reaction solution dilutes with EtOAc (200mL), separate organic phase, water extracts with EtOAc (100mL * 3), merge organic phase, use successively saturated sodium bicarbonate solution (100mL * 3), the saturated NaCl aqueous solution (50mL * 3) washing, anhydrous sodium sulfate drying, the concentrated about 2.3g of white solid crude product IV-1-2 that obtains not purifiedly directly carries out next step reaction.
7. prepare compound V-2
Crude product IV-1-2 (2.3g) is dissolved among the THF (100mL), add HOAc/MeOH (1: 1) under the ice bath (50mL), 50 ℃ of lower reaction 2h, after the TLC detection reaction is complete, reaction solution is concentrated, gains are dissolved with EtOAc (200mL), use successively saturated sodium bicarbonate solution (100mL * 6), the saturated NaCl aqueous solution (100mL * 3) washing, anhydrous sodium sulfate drying, concentrated, obtain white foam shape solid (V-2,2.2g, two step total recoverys: 96.6%) through column chromatography (ethyl acetate/petroleum ether=1: 3);
1H NMR (400MHz, CDCl
3) δ 8.10 (d, J=7.3Hz, 2H, Ph-H), 7.62 (t, J=7.3Hz, 1H, Ph-H), 7.50 (t, J=7.8Hz, 2H, Ph-H), 7.43-7.32 (m, 5H, Ph-H), (6.22 broad t, J=8.8Hz, 1H, H-13), 5.67 (d, J=7.3Hz, 1H, H-2), 5.59 (s, 1H, H-10), 5.42 (broad d, J=9.8Hz, 1H, CON
H), 5.28 (broad d, J=8.3Hz, 1H, H-3 '), 4.96 (d, J=8.8Hz, 1H, H-5), 4.76 (d, J=11.7Hz, 1H, CH
3SC
HHO), 4.72 (d, J=11.7Hz, 1H, CH
3SCH
HO), 4.67 (d, J=11.7Hz, 1H, CH
3SCH
HO), 4.61 (d, J=11.7Hz, 1H, CH
3SCH
HO), 4.31 (d, J=8.3Hz, 1H, H-20a), (4.25 dd, J=10.2,6.3Hz, 1H, H-7), (4.18 d, J=8.3Hz, 1H, H-20b), 3.87 (d, J=6.8Hz, 1H, H-3), 3.72 (dd, J=14.1,6.8Hz, 1H, H-2 '), 3.44 (d, J=5.4Hz, 1H, O
H-2 '), 2.83-2.76 (m, 1H), 2.37 (s, 3H, C
H 3CO in C-4), 2.31-2.27 (m, 2H), 2.21 (s, 3H, SC
H 3 ), 2.16 (s, 3H, SC
H 3 ), 2.01 (s, 3H, C
H 3In C-18), 1.89-1.83 (m, 1H), 1.75 (s, 3H, C
H 3In C-19), 1.37 (s, 9H,
Me 3C), 1.23 (s, 3H, C
H 3 ), 1.21 (s, 3H, C
H 3 ).
13C NMR (100MHz, CDCl
3): δ 204.5,171.4, and 167.0,155.3,139.6,134.5,133.7,130.1,129.2,128.8,128.6,128.0,126.8,83.8,81.4,80.2,78.7,77.8,76.6,74.6,73.8,72.5,72.3,58.5,57.3,47.1,43.3,35.2,32.9,28.2,26.6,22.6,20.7,18.4,15.7,14.2,13.8,10.7.
8. preparation Compound C abazitaxel (XRP6258) (V)
With V-2 (2.2g, 2.4mmol) be dissolved in 95% the ethanol (150mL), add Raneynickel (about 5 grams), under 3 normal atmosphere hydrogen, 50 ℃ are stirred 12h, after the thin-layer chromatography detection reaction is complete, with the reaction solution suction filtration, filtrate is concentrated, and enriched material is with a large amount of ethyl acetate drip washing filter cakes, filtrate is diluted with ethyl acetate (500mL), with saturated sodium-chloride water solution (150mL * 3) washing, anhydrous sodium sulfate drying, concentrated, obtain white foam shape solid Cabazitaxel (XRP6258) (V) (1.3g, yield: 66.0%) through column chromatography (ethyl acetate/petroleum ether=1: 3).
Claims (8)
1. method for preparing paclitaxel kind anti-cancer drugs Cabazitaxel XRP6258, described CabazitaxelXRP6258 has the structure of formula (V), it is characterized in that, said method comprising the steps of:
A. remove acetyl baccatin III (I with 10-, 10-DAB) be initial reactant, carry out synchronously Pummerer and reset and the Swern oxidizing reaction, the C-7, the C-10 position hydroxyl first sulphur methylene radical (MTM) that obtain I with high yield and regioselectivity are changed and C-13 hydroxyl oxidize product II;
B. intermediate II is obtained intermediate III through C-13 position carbonyl reduction;
C. the intermediate III that obtains is docked with various types of side chains and obtain docking product intermediate (IV-1) and (IV-2), its pair methylthio group that then removes first obtain respectively (V-1) and (V-2) after remove Side chain protective group and obtain Cabazitaxel XRP6258 (V), perhaps remove first two methylthio groups that its Side chain protective group obtains removing after (V-3) parent nucleus and obtain products C abazitaxel XRP6258 (V);
2. by method claimed in claim 1, it is characterized in that, reagent used in Pummerer rearrangement among the described step a and the Swern oxidizing reaction is methyl-sulphoxide/acid anhydrides, and used catalyzer is various organic acids or mineral acid, and temperature of reaction is between 25 ℃ to 80 ℃.
3. by method claimed in claim 2, it is characterized in that described catalyzer is acetic acid or p-toluenesulphonic acids.
4. by method claimed in claim 1, it is characterized in that the reagent that the C-13 position carbonyl reduction among the described step b adopts is sodium borohydride, temperature of reaction is between-10 ℃ to 25 ℃.
5. by method claimed in claim 1, it is characterized in that the various side chains among the described step c comprise: with the beta-lactam of different protecting groups, five yuan of oxazolidine carboxylic-acids, straight-chain carboxylic acid's class etc.
6. by each described method in the claim 1～5; it is characterized in that; described protecting group is the silicon ether protecting group that the alkyl or aryls such as t-Butyldimethylsilyl (TBS), triethyl silica-based (TES), triisopropylsilyl (TIPS), trimethyl silicon based (TMS) replace, perhaps methoxyl methyl (MOM) or 1-ethoxyethyl group (EE).
7. by each described method in the claim 1～5, it is characterized in that, the reagent that piptonychia sulfenyl among the described step c uses is Raney's nickel (Raney-nickel)/hydrogen, used solvent is selected from the group that is comprised of tetrahydrofuran (THF), ethanol, methyl alcohol and composition thereof, and temperature of reaction is between 25 ℃ to 60 ℃;
8. each described method is characterized in that according to claim 1～5, and the reagent that the deprotection base among the described step c adopts is tetrabutyl ammonium fluoride (TBAF), hydrogen fluoride/pyridine, acetic acid/methyl alcohol or acetic acid/zinc.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044364A (en) * | 2013-01-07 | 2013-04-17 | 重庆泰濠制药有限公司 | Cabazitaxel amorphous crystal and preparation method thereof |
| CN103421036A (en) * | 2012-05-17 | 2013-12-04 | 上海希迈医药科技有限公司 | Cabazitaxel intermediate as well as preparation method and application thereof |
| WO2015096553A1 (en) * | 2013-12-24 | 2015-07-02 | 于跃 | Anti-multidrug resistance taxane anti-tumour compound and preparation method thereof |
| CN104945320A (en) * | 2014-03-31 | 2015-09-30 | 于跃 | Quinolinone alkaloid derivatives with anti-RSV activity and preparation method thereof |
| CN104945319A (en) * | 2014-03-31 | 2015-09-30 | 于跃 | Quinolinone alkaloid compound and application thereof as antiviral drug |
| CN103421036B (en) * | 2012-05-17 | 2016-11-30 | 上海创诺制药有限公司 | A kind of Cabazitaxel intermediate and its preparation method and application |
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| CN103421036A (en) * | 2012-05-17 | 2013-12-04 | 上海希迈医药科技有限公司 | Cabazitaxel intermediate as well as preparation method and application thereof |
| CN103421036B (en) * | 2012-05-17 | 2016-11-30 | 上海创诺制药有限公司 | A kind of Cabazitaxel intermediate and its preparation method and application |
| CN103044364A (en) * | 2013-01-07 | 2013-04-17 | 重庆泰濠制药有限公司 | Cabazitaxel amorphous crystal and preparation method thereof |
| CN103044364B (en) * | 2013-01-07 | 2016-01-20 | 重庆泰濠制药有限公司 | Amorphous crystalline substance of a kind of Cabazitaxel and preparation method thereof |
| WO2015096553A1 (en) * | 2013-12-24 | 2015-07-02 | 于跃 | Anti-multidrug resistance taxane anti-tumour compound and preparation method thereof |
| CN104945320A (en) * | 2014-03-31 | 2015-09-30 | 于跃 | Quinolinone alkaloid derivatives with anti-RSV activity and preparation method thereof |
| CN104945319A (en) * | 2014-03-31 | 2015-09-30 | 于跃 | Quinolinone alkaloid compound and application thereof as antiviral drug |
| CN104945320B (en) * | 2014-03-31 | 2019-01-15 | 扬州蓝色生物医药科技有限公司 | Alcaloid-derivatives and its application as drug |
| CN104945319B (en) * | 2014-03-31 | 2019-03-29 | 扬州蓝色生物医药科技有限公司 | A kind of quinolinone alkaloid class compound and its application as antiviral drugs |
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