CN103012330A - Preparation method of taxol anticancer drugs XRP6258 - Google Patents
Preparation method of taxol anticancer drugs XRP6258 Download PDFInfo
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- CN103012330A CN103012330A CN2011102875752A CN201110287575A CN103012330A CN 103012330 A CN103012330 A CN 103012330A CN 2011102875752 A CN2011102875752 A CN 2011102875752A CN 201110287575 A CN201110287575 A CN 201110287575A CN 103012330 A CN103012330 A CN 103012330A
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N OC(c1ccccc1)=O Chemical compound OC(c1ccccc1)=O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 0 *C(*)(*[C@]1c2ccccc2)[U][C@]1C(O)=N Chemical compound *C(*)(*[C@]1c2ccccc2)[U][C@]1C(O)=N 0.000 description 3
- XMIIGOLPHOKFCH-UHFFFAOYSA-N OC(CCc1ccccc1)=O Chemical compound OC(CCc1ccccc1)=O XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 3
- JLEHSYHLHLHPAL-UHFFFAOYSA-N CC(C)(C)NC(N)=O Chemical compound CC(C)(C)NC(N)=O JLEHSYHLHLHPAL-UHFFFAOYSA-N 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
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Abstract
The invention belongs to the field of drug synthesis, and relates to a method for preparing taxol anticancer drugs 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, sequentially removing methylthio, reducing C-13 bit carbonyl or sequentially reducing C-13 bit carbonyl and removing methylthio to obtain a mother nucleus (IV) of the product XRP6258, carrying out butt joint with side chains with various types and removing a side-chain protecting group to obtain a product Cabazitaxel (V). The method disclosed by the invention has the advantages of being high in efficiency during a preparation process, 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; relate to paclitaxel kind anti-cancer drugs; be specifically related to the preparation method of paclitaxel kind anti-cancer drugs Cabazitaxel (XRP6258); specifically; it is a kind of novel method of the 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 its semi-synthetic analogue Docetaxel (Docetaxel) are the most effectively one of cancer therapy drugs of up to now human discovery, continue the end of the year 1992 after U.S. listing, successively go through to go on the market in more than 40 countries, and be widely used in mammary cancer, lung cancer, cancer of the stomach, esophagus cancer, ovarian cancer etc. as a line cancer therapy drug.Although they have significant anticancer therapeutic, the same with other chemotherapeutics, taxol is for multidrug resistance (MDR) tumour non-activity almost, and this also is the important factor that the taxol medication causes the chemotherapy failure.Thereby it is domestic and international pharmaceutical science man's study hotspot that exploitation still keeps the taxanes cancer therapy drug of curative effect for multidrug resistance of tumor always.
Cabazitaxel (XRP6258) is the bearing taxanes by the research and development of French Sanofi-Aventis company, and its constructional feature is that the C-7 of docetaxel, the two methyl-etherifieds of C-10 position hydroxyl are modified.External Cabazitaxel (XRP6258) has the cytotoxic activity suitable with docetaxel to P388, HL60, KB, Calc18 tumour, yet, it crosses the tumor cell line of expression to the P-glycoprotein of taxol resistance, has significant activity such as P388/DOX, P388/TXT, HL60/TAX, Calc18/TXT etc.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.Except prostate cancer, it is present that Cabazitaxel also may become the new selection for the treatment of other malignant tumours, and the semisynthesis of Cabazitaxel 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.
It is too low that the method for the above-mentioned XRP6258 of preparation all has yield, and the defective such as purification difficult (multistep column chromatography), synthetic route are oversize has limited industrial large-scale preparation and application.
Summary of the invention
The purpose of this invention is to provide a kind of new method for preparing s-generation taxanes PTS XRP6258, 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.
Preparation method of the present invention; by following reaction formula; carry out synchronously Pummerer Rearrangement and Swern Oxidation reaction by methyl-sulphoxide/acetic anhydride; obtain the C-7 of 10-deacetylation bar card fourth III (I) with high yield and regioselectivity; the two MTMization of C-10 position hydroxyl and C-13 position hydroxyl oxidize product II; then transform the parent nucleus (IV) that obtains XRP6258 through piptonychia sulfenyl and two steps of C-13 position carbonyl reduction successively; or pass through successively the parent nucleus (IV) that C-13 position carbonyl reduction and piptonychia sulfenyl obtain product XRP6258, then dock and slough Side chain protective group with various types of side chains and obtain product XRP6258 (V):
Particularly, the preparation method of a kind of paclitaxel kind anti-cancer drugs XRP6258 of the present invention is characterized in that, it comprises step:
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 passed through first the piptonychia sulfenyl and obtain intermediate III, again C-13 position carbonyl reduction is obtained the parent nucleus IV of XRP6258, or pass through the parent nucleus IV that C-13 position carbonyl reduction and piptonychia sulfenyl also can obtain XRP6258 first;
C. the parent nucleus IV that obtains is docked with various types of side chains, last deprotection base obtains product XRP6258 (V).
Among the present invention, reagent used in the described Pummerer rearrangement of 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, preferred catalyst is acetic acid or p-toluenesulphonic acids.
Among the present invention, the reagent that the described piptonychia sulfenyl of step b 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, the reagent that the described C-13 of step b position carbonyl reduction adopts is sodium borohydride, and temperature of reaction is between-10 ℃ to 25 ℃.
Among the present invention, the described various side chains of step c comprise: with the beta-lactam of different protecting groups, five yuan of oxazolidine carboxylic-acids, straight-chain carboxylic acid's class etc.; 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).
Among the present invention, the reagent that the described deprotection base of step c adopts is tetrabutyl ammonium fluoride (TBAF), hydrogen fluoride/pyridine, acetic acid/methyl alcohol, acetic acid/zinc etc.
The characteristics of the inventive method 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 is provided:: the C-7 of preparation 10-deacetylation bar card fourth III (I) and the parent nucleus (IV) of the bis-alkylated XRP6258 of C-10 position hydroxyl;
Gordian technique also is provided: carry out the protecting group switching strategy at 7-OH, 10-OH, 13-OH respectively so that with 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 herein.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 describes technical scheme of the present invention in detail.
Concrete synthetic method:
This route is to 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 is prepared product II, and 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 acids etc.), and temperature of reaction is between 20 ℃ to 60 ℃, and optimal reaction temperature is 25 ℃.
The intermediate II crude product is dissolved in the ethanol, makes catalyzer with Raney's nickel, carry out the hydrogenolysis desulphurization reaction under the room temperature, crude product obtains white powder parent nucleus III sterling through simple recrystallization, and three step total recoverys are about 70%.Wherein, used solvent is the single or mixed solvents such as tetrahydrofuran (THF), ethanol, methyl alcohol, and temperature of reaction is between 25 ℃ to 60 ℃.
The method of utilizing document to report is reacted intermediate III and sodium borohydride (5.0eq to 10.0eq) under ice bath, obtain the pale solid intermediate compound IV that C-13 position carbonyl is reduced with high regioselectivity and stereoselectivity, and 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 (IV) also can obtain intermediate (III-1) through the piptonychia sulfenyl first and then obtain through the reduction of C-13 position carbonyl, and working method is the same.
Parent nucleus IV 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 product IV-1 product with the transformation efficiency more than 90%; then remove the pendant hydroxyl group protecting group, column chromatography purification obtains XRP6258 white foam shape solid.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 compound IV).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 IV 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 docking product IV-2 crude product with the transformation efficiency more than 90%; then remove Side chain protective group, column chromatography purification obtains XRP6258 white foam shape solid.Wherein, R
3, R
4Represent 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 IV is carried out condensation from the straight-chain carboxylic acid (1.0-2.0eq) that C-2 position hydroxyl is protected by different protecting groups under room temperature; obtain docking product IV-3 crude product 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 compound IV).The blocking group R of described C-2 position
2The 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
2Be MOM), during the protecting group such as EE, it is acetic acid/methyl alcohol etc. that the protecting group of this moment removes reagent.
Compare with background technology, 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 used reagent such as acetic anhydride, acetic acid, methyl alcohol and ethanol of the present invention 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-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]
+.
2. preparation compound III
With II (6.6g, 10.0mmol) be dissolved in 95% the ethanol (150mL), add Raney's nickel (about 3g), under 3 normal atmosphere hydrogen, 55 ℃ 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 with ethyl acetate (500mL) dilution, with saturated sodium-chloride water solution (150mL * 3) washing, anhydrous sodium sulfate drying, concentrated, crude product obtains white powder solid product III (4.8g, yield: 83.0%) with recrystallization from ethyl acetate/petroleum ether;
1H-NMR (400MHz, CDCl
3): δ 8.06 (d, 2H, J=7.0Hz, Ph-H), 7.62 (t, 1H, J=7.4Hz, Ph-H), 7.48 (t, 2H, J=7.8Hz, Ph-H), (5.64 d, 1H, J=7.1Hz, H-2), 5.30 (s, 1H, H-10), 5.00-4.96 (m, 1H, H-5), 4.32 (d, 1H, J=8.6Hz, H-20a), 4.12 (d, 1H, J=8.2Hz, H-20b), (3.92-3.88 m, 1H, H-7and H-3), 3.51 (s, 3H, OC
H 3), 3.32 (s, 3H, OC
H 3), 2.91 (d, 1H, J=20.0Hz, H-14a), 2.75-2.68 (m, 1H, H-6a), 2.66 (d, 1H, J=20.0Hz, H-14b), 2.20 (s, 3H, C
H 3CO), 2.12 (s, 3H, C
H 3In C-18), 1.81-1.75 (m, 1H, H-6b), 1.68 (s, 3H, C
H 3In C-19), 1.25 (s, 3H, C
H 3), 1.22 (s, 3H, C
H 3);
ESI-MS(m/z)：571.3[M+H]
+(Calcd?570.3)、593.2[M+Na]
+.
3. preparation compound IV
With III (2.8g; 5.0mmol) be dissolved in dry tetrahydrofuran (THF)/methyl alcohol (5/1) (100mL) in; argon shield; slowly drip sodium borohydride (3.6g under the ice bath; 100.0mmol) tetrahydrofuran solution (100mL); 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 (200mL) 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 the hydrochloric acid (100mL * 3) of 1M; saturated sodium bicarbonate aqueous solution (100mL * 3); saturated sodium-chloride water solution (100mL * 3) washing, anhydrous sodium sulfate drying, concentrated.Crude product obtains white powder solid product IV (2.6g, yield: 91.0%) with recrystallization from ethyl acetate/petroleum ether;
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).
4. prepare compound III-1
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 III-1 (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-10and 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);
ESI-MS(m/z)：665.2[M+H]
+(Calcd?664.2)、687.2[M+Na]
+.
5. prepare compound III-1
With III-1 (3.3g, 5.0mmol) be dissolved in 95% the ethanol (100mL), add Raney's nickel (about 3g), under 3 normal atmosphere hydrogen, 55 ℃ 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 with ethyl acetate (500mL) dilution, with saturated sodium-chloride water solution (150mL * 3) washing, anhydrous sodium sulfate drying, concentrated, obtain white powder solid product IV (2.5g, yield: 88.3%) with recrystallization from ethyl acetate/petroleum ether;
6. prepare compound IV-1-1
With IV (1.43g; 2.5mmol) and X-6 (1.2g; 3.3mmol) be dissolved among the dry THF (300mL); 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 white solid crude product IV-1-1 (2.8g) that obtains not purifiedly directly carries out next step reaction;
1HNMR (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 3C and 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).
7. prepare compound IV-1-2
With IV (1.43g; 2.5mmol) and Y-6 (1.1g; 3.3mmol) be dissolved among the dry THF (300mL); 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 white solid crude product VII-1-2 (2.4g) that obtains not purifiedly directly carries out next step reaction;
8. prepare compound V
Crude product IV-1-1 (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 broadt, 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]
+.
9. prepare compound V
Crude product IV-1-2 (2.4g) 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 Cabazitaxel (XRP6258, V) through column chromatography (ethyl acetate/petroleum ether=1: 3), (2.0g, two step total recoverys: 93.8%).
Claims (7)
1. the preparation method of a paclitaxel kind anti-cancer drugs XRP6258, described anticarcinogen XRP6258 has the structure of formula (V), it is characterized in that, and described method comprises step:
A. remove acetyl baccatin III (I with 10-, 10-DAB) be initial reactant, carry out synchronously Pummerer and reset and the 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. intermediate II is obtained intermediate III through the piptonychia sulfenyl first, again C-13 position carbonyl reduction is obtained the parent nucleus IV of XRP6258; Or also can obtain first the parent nucleus IV of XRP6258 through C-13 position carbonyl reduction and piptonychia sulfenyl;
C. the parent nucleus IV that obtains is docked with various types of side chains, last deprotection base obtains product XRP6258 (V),
2. method according to claim 1 is characterized in that, reagent used in the Pummerer rearrangement of described step a and the Swern oxidizing reaction is methyl-sulphoxide/acid anhydrides, and used catalyzer is organic acid or mineral acid, and temperature of reaction is between 25 ℃ to 80 ℃.
3. method according to claim 2 is characterized in that, described catalyzer is acetic acid or p-toluenesulphonic acids.
4. method according to claim 1, it is characterized in that, the reagent that the piptonychia sulfenyl of described step b 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 ℃; The reagent that described C-13 position carbonyl reduction adopts is sodium borohydride, and temperature of reaction is between-10 ℃ to 25 ℃.
5. method according to claim 1 is characterized in that, the various side chains of described step c comprise: with the beta-lactam of different protecting groups, five yuan of oxazolidine carboxylic-acids or straight-chain carboxylic acid's class.
6. such as each described method in the claim 1～5; it is characterized in that; described protecting group is the silicon ether protecting group that t-Butyldimethylsilyl (TBS), triethyl silica-based (TES), triisopropylsilyl (TIPS) or trimethyl silicon based alkyl or aryl replace, or methoxyl methyl (MOM) or 1-ethoxyethyl group (EE).
7. each described method according to claim 1～5 is characterized in that: the reagent that the deprotection base of described step c adopts is tetrabutyl ammonium fluoride (TBAF), hydrogen fluoride/pyridine, acetic acid/methyl alcohol or acetic acid/zinc etc.
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Cited By (4)
| 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 |
| 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 |
| CN107266528A (en) * | 2016-04-06 | 2017-10-20 | 重庆大学 | A kind of method for preparing natural products Aetheramide A and Aetheramide B |
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| WO2002070498A1 (en) * | 2001-03-05 | 2002-09-12 | Aventis Pharma, S.A. | Methods for preparing new taxoids and pharmaceutical compositions containing them |
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| CN1270586A (en) * | 1997-11-18 | 2000-10-18 | 阿文蒂斯药物股份有限公司 | Method for preparing derivatives of the taxoid class |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN107266528A (en) * | 2016-04-06 | 2017-10-20 | 重庆大学 | A kind of method for preparing natural products Aetheramide A and Aetheramide B |
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