CN103172654B - Bearing taxanes and preparation method thereof - Google Patents
Bearing taxanes and preparation method thereof Download PDFInfo
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- CN103172654B CN103172654B CN201110434548.3A CN201110434548A CN103172654B CN 103172654 B CN103172654 B CN 103172654B CN 201110434548 A CN201110434548 A CN 201110434548A CN 103172654 B CN103172654 B CN 103172654B
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- cabazitaxel
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 229940045698 antineoplastic Taxanes Drugs 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 83
- 238000006243 chemical reaction Methods 0.000 claims abstract description 62
- 239000002904 solvent Substances 0.000 claims description 37
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- 239000003153 chemical reaction reagent Substances 0.000 claims description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 claims description 16
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 15
- 230000001035 methylating Effects 0.000 claims description 14
- YNESATAKKCNGOF-UHFFFAOYSA-N Lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical group CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 claims description 11
- 150000002460 imidazoles Chemical class 0.000 claims description 10
- 239000002994 raw material Substances 0.000 claims description 10
- INQOMBQAUSQDDS-UHFFFAOYSA-N Methyl iodide Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- 125000003944 tolyl group Chemical group 0.000 claims description 5
- 238000006482 condensation reaction Methods 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N N,N′-Dicyclohexylcarbodiimide Substances C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- 229960001573 cabazitaxel Drugs 0.000 abstract description 27
- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 abstract description 26
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000002194 synthesizing Effects 0.000 abstract description 3
- 238000000034 method Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- 239000007787 solid Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 9
- 238000006884 silylation reaction Methods 0.000 description 9
- -1 Cabazitaxel Compound Chemical class 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 230000035693 Fab Effects 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 230000002829 reduced Effects 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-N HF Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 5
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- IUBQJLUDMLPAGT-UHFFFAOYSA-N Potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 4
- WRIKHQLVHPKCJU-UHFFFAOYSA-N Sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 0 C[C@@](C([C@@]1(C)[C@@](C[C@@]2O)OC1)[C@]2(C)C([C@@]1O)=O)[C@](*)(C2)C(C)(C)C1=C(C)[C@@]2O Chemical compound C[C@@](C([C@@]1(C)[C@@](C[C@@]2O)OC1)[C@]2(C)C([C@@]1O)=O)[C@](*)(C2)C(C)(C)C1=C(C)[C@@]2O 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N Hexamethylphosphoramide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000005712 crystallization Effects 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- OVMSOCFBDVBLFW-VHLOTGQHSA-N 5β,20-epoxy-1,7β,13α-trihydroxy-9-oxotax-11-ene-2α,4α,10β-triyl 4,10-diacetate 2-benzoate Chemical compound O([C@@H]1[C@@]2(C[C@H](O)C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)O)C(=O)C1=CC=CC=C1 OVMSOCFBDVBLFW-VHLOTGQHSA-N 0.000 description 2
- APAROGMVGYJABW-UHFFFAOYSA-N B(O)(O)O.CF Chemical compound B(O)(O)O.CF APAROGMVGYJABW-UHFFFAOYSA-N 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N Dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910004161 SiNa Inorganic materials 0.000 description 2
- 229940091252 Sodium supplements Drugs 0.000 description 2
- 230000000259 anti-tumor Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 2
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- PKAUVIXBZJUYRV-UHFFFAOYSA-N methane;hydroiodide Chemical compound C.I PKAUVIXBZJUYRV-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1H-pyrrole Chemical compound C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 1
- DCTOHCCUXLBQMS-UHFFFAOYSA-N 1-undecene Chemical compound CCCCCCCCCC=C DCTOHCCUXLBQMS-UHFFFAOYSA-N 0.000 description 1
- UIQMVEYFGZJHCZ-SSTWWWIQSA-N Antorphin Chemical compound C([C@@H](N(CC1)CC=C)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 UIQMVEYFGZJHCZ-SSTWWWIQSA-N 0.000 description 1
- CQADMXFIYFJOCH-UGFPFTKESA-N CC(C)(C)OC(N([C@H]1c2ccccc2)C(c(cc2)ccc2OC)O[C@H]1C(O[C@@H](C1)C(C)=C([C@H](C([C@](C)([C@H](C[C@H]2OC[C@H]22)O)[C@@]2([C@@H]2OC(c3ccccc3)=O)/N=[O]\C(C)=O)=O)OC)C(C)(C)[C@@]12O)=O)=O Chemical compound CC(C)(C)OC(N([C@H]1c2ccccc2)C(c(cc2)ccc2OC)O[C@H]1C(O[C@@H](C1)C(C)=C([C@H](C([C@](C)([C@H](C[C@H]2OC[C@H]22)O)[C@@]2([C@@H]2OC(c3ccccc3)=O)/N=[O]\C(C)=O)=O)OC)C(C)(C)[C@@]12O)=O)=O CQADMXFIYFJOCH-UGFPFTKESA-N 0.000 description 1
- RVDZZBRCGAJPMB-FNUGOGNPSA-N CC(C)(C)OC(N([C@H]1c2ccccc2)C(c(cc2)ccc2OC)O[C@H]1C(O[C@@H](C1)C(C)=C([C@H](C([C@](C)([C@H](C[C@H]2OC[C@H]22)OC)[C@@]2([C@@H]2OC(c3ccccc3)=O)/N=[O]\C(C)=O)=O)OC)C(C)(C)[C@@]12O)=O)=O Chemical compound CC(C)(C)OC(N([C@H]1c2ccccc2)C(c(cc2)ccc2OC)O[C@H]1C(O[C@@H](C1)C(C)=C([C@H](C([C@](C)([C@H](C[C@H]2OC[C@H]22)OC)[C@@]2([C@@H]2OC(c3ccccc3)=O)/N=[O]\C(C)=O)=O)OC)C(C)(C)[C@@]12O)=O)=O RVDZZBRCGAJPMB-FNUGOGNPSA-N 0.000 description 1
- DMSZORWOGDLWGN-UHFFFAOYSA-N CTK1A3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N Docetaxel Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 210000002307 Prostate Anatomy 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229930014667 baccatin III Natural products 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- KVXNKFYSHAUJIA-UHFFFAOYSA-M ethoxyethane;acetate Chemical compound CC([O-])=O.CCOCC KVXNKFYSHAUJIA-UHFFFAOYSA-M 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000004881 tumor cells Anatomy 0.000 description 1
Abstract
The present invention relates to a kind of bearing taxanes and preparation method thereof, more particularly to for preparing the intermediate Formula V compound of Cabazitaxel, its preparation method, and the method preparing Cabazitaxel with this compound.Prepare the process of Cabazitaxel with the intermediate of the present invention, the response time in each step is greatly shortened, and reaction yield is greatly improved, and greatly reduces the synthesis cost of Cabazitaxel.
Description
Technical field
The present invention relates to a kind of new bearing taxanes, more particularly to the intermediate for preparing Cabazitaxel
Compound, its preparation method, and the method preparing Cabazitaxel with this compound.
Background technology
Bearing taxanes has the strongest anti-tumor activity, has this compounds list marketing at present, such as Ramulus et folium taxi cuspidatae
Alcohol, Docetaxel and Cabazitaxel etc., they have good inhibitory activity to various solid tumor cells.Wherein, kappa he
Match (structure is as follows) is that this medicine is to prostate by the taxane anti-tumor medicament of match Norfin, Inc of France exploitation listing
Cancer patients with terminal curative effect is preferable, and compared with other antitumor drug, this medicine can significantly improve the life of carcinoma of prostate patients with terminal
Life power, extends patient vitals.
Cabazitaxel
International application WO9630355 discloses two kinds of methods preparing Cabazitaxel, but the yield of both approaches is all
The lowest, considerably increase the synthesis cost of Cabazitaxel, need to find better method, to improve the yield of Cabazitaxel,
Reduce its cost.
Summary of the invention
The compound of one aspect of the present invention a kind of Formula V of offer:
Formula V,
Wherein, R1Selected from silylation, preferably TMS, triethyl silyl, tri isopropyl silane base, the tert-butyl group
Dimethylsilyl, tert-butyldiphenylsilanyl, more preferably triethyl silyl.
In a specific embodiment of the present invention, it is provided that compound 1:
Further aspect of the present invention provides the preparation method of a kind of Formula V compound, comprises the steps:
(1) 10-DAB is that raw material reacts with silylating reagent, prepares formula III compound,
(2) formula III compound reacts with methylating reagent, prepares formula IV compound,
(3) formula IV compound and Formula II compound carry out condensation reaction, prepare Formula V compound,
Wherein, R1Selected from silylation, preferably TMS, triethyl silyl, tri isopropyl silane base, the tert-butyl group
Dimethylsilyl, tert-butyldiphenylsilanyl, more preferably triethyl silyl.
The silylating reagent used in step (1) is selected from trim,ethylchlorosilane, chlorotriethyl silane, triisopropyl chlorine silicon
Alkane, tert-butyl chloro-silicane, tert-butyl diphenyl chlorosilane etc., preferably chlorotriethyl silane.
The solvent used in step (1) is polar solvent, selected from DMF, pyridine, acetone or acetonitrile etc., preferably DMF or pyrrole
Pyridine.
Reaction temperature in step (1) is 0-20 DEG C, preferably 0 DEG C.
The reaction of step (1) is carried out in the basic conditions, and alkali is selected from triethylamine, pyridine or imidazoles etc., prioritizing selection imidazoles
Or pyridine.
In a specific embodiment of the present invention, the silylating reagent used in step (1) is chlorotriethyl silane,
The solvent used is pyridine, and reaction temperature is 0 DEG C.
In the another embodiment of the present invention, the silylating reagent used in step (1) is triethylchloro-silicane
Alkane, the solvent of use is DMF, and alkali is imidazoles, and reaction temperature is 0 DEG C.
The methylating reagent used in step (2) is selected from iodomethane, dimethyl sulfate, fluoromethane borate etc., preferably iodine
Methane.
The reaction of step (2) is carried out in the presence of a basic, alkaline matter selected from hydrofining, sodium hydride, LiHMDS,
NaHMDS, KHMDS etc., preferably LiHMDS.
Reaction dissolvent in step (2) is selected from DMF, HMPA, oxolane etc., preferably oxolane.
Reaction temperature in step (2) is-40-0 DEG C, preferably 0 DEG C.
In a specific embodiment of the present invention, the methylating reagent used in step (2) is iodomethane, use
Solvent is oxolane, and alkaline matter is LiHMDS, and reaction temperature is 0 DEG C.
One or more in DCC, DPC, EDCI or DMAP of the condensing agent used in step (3), preferably DCC and
DMAP。
The mol ratio of DCC and DMAP used in step (3) is 2: 1.
In step (3), reaction dissolvent is selected from ethyl acetate, benzene, toluene, dichloromethane etc., preferably toluene or dichloromethane.
In step (3), reaction temperature is 25-80 DEG C, preferably 25 DEG C.
In one detailed description of the invention of the present invention, the condensing agent used in step (3) is DCC and DMAP, use molten
Agent is toluene, and reaction temperature is 25 DEG C.
In a specific embodiment of the present invention, the silylating reagent used in step (1) is chlorotriethyl silane,
The solvent used is pyridine, and reaction temperature is 0 DEG C；The methylating reagent used in step (2) is iodomethane, and the solvent of use is
Oxolane, alkaline matter is LiHMDS, and reaction temperature is 0 DEG C；The condensing agent used in step (3) is DCC and DMAP, uses
Solvent be toluene, reaction temperature is 25 DEG C.
In a specific embodiment of the present invention, the silylating reagent used in step (1) is chlorotriethyl silane,
The solvent used is DMF, and alkali is imidazoles, and reaction temperature is 0 DEG C；The methylating reagent used in step (2) is iodomethane, uses
Solvent be oxolane, alkaline matter is LiHMDS, and reaction temperature is 0 DEG C；The condensing agent used in step (3) be DCC and
DMAP, the solvent of use is toluene, and reaction temperature is 25 DEG C.
Further aspect of the present invention provides the preparation method of compound 1, comprises the steps:
(1) 10-DAB reacts in the basic conditions with chlorotriethyl silane, generates compound 3,
(2) compound 3 reacts in the presence of a basic with iodomethane, generates compound 4,
(3) there is condensation reaction in compound 4 and compound 2 in the presence of condensing agent, generates compound 1,
In one detailed description of the invention of the present invention, the solvent used in step (1) is pyridine, and reaction temperature is 0 DEG C.
In one detailed description of the invention of the present invention, the solvent used in step (1) is DMF, and alkali is imidazoles, reaction temperature
Degree is 0 DEG C.
In one detailed description of the invention of the present invention, the solvent used in step (2) is oxolane, and alkaline matter is
LiHMDS, reaction temperature is 0 DEG C.
In a specific embodiment of the present invention, the condensing agent used in step (3) is DCC and DMAP, use
Solvent is toluene, and reaction temperature is 25 DEG C.
Further aspect of the present invention provides Formula V compound for preparing the purposes of Cabazitaxel.
Further aspect of the present invention provides compound 1 for preparing the purposes of Cabazitaxel.
Further aspect of the present invention provides a kind of method being prepared Cabazitaxel by Formula V compound, comprises the steps:
A () Formula V compound is taken off silylation protection group and is prepared compound 6,
B () compound 6 and methylating reagent react and prepare compound 7,
C () is prepared Cabazitaxel by compound 7,
Wherein, R1Selected from silylation, preferably TMS, triethyl silyl, tri isopropyl silane base, the tert-butyl group
Dimethylsilyl, tert-butyldiphenylsilanyl, more preferably triethyl silyl.
Wherein, the solvent used in step (a) is DCM；Reaction temperature is 0-20 DEG C；Reaction is deposited at fluohydric acid gas-triethylamine
Under carry out.
The solvent used in step (b) is DMSO；Reaction temperature is 0-20 DEG C, preferably 0 DEG C；The alkaline matter used is hydrogen
Change sodium.
The solvent used in step (c) is HCl/ ethanol；Reaction temperature is-10-10 DEG C, preferably-2-5 DEG C.
In the detailed description of the invention of the present invention, it is provided that the method being prepared Cabazitaxel by compound 1, including walking as follows
Rapid:
A () compound 1 is taken off silylation protection group and is prepared compound 6,
B () compound 6 and methylating reagent react and prepare compound 7,
C () is prepared Cabazitaxel by compound 7,
Wherein, the solvent used in step (a) is DCM；Reaction temperature is 0-20 DEG C；Reaction is deposited at fluohydric acid gas-triethylamine
Under carry out.
The solvent used in step (b) is DMSO；Reaction temperature is 0-20 DEG C, preferably 0 DEG C；The alkaline matter used is hydrogen
Change sodium.
The solvent used in step (c) is HC1/ ethanol；Reaction temperature is-10-10 DEG C, preferably-2-5 DEG C.
Further aspect of the present invention offer compound 6:
Further aspect of the present invention provides the preparation method of compound 6, takes off silylation protection group system including by Formula V compound
For obtaining compound 6,
Wherein, R1Selected from silylation, preferably TMS, triethyl silyl, tri isopropyl silane base, the tert-butyl group
Dimethylsilyl, tert-butyldiphenylsilanyl, more preferably triethyl silyl.
The solvent used in reaction is DCM；Reaction temperature is 0-20 DEG C；Reaction is carried out in the presence of fluohydric acid gas-triethylamine.
In a specific embodiment of the present invention, the preparation method of compound 6 includes compound 1 is taken off triethyl group
Protected silane base:
The solvent used in reaction is DCM；Reaction temperature is 0-20 DEG C；Reaction is carried out in the presence of fluohydric acid gas-triethylamine.
Further aspect of the present invention provides compound 6 for preparing the purposes of Cabazitaxel.
Further aspect of the present invention provides a kind of method being prepared Cabazitaxel by compound 6, comprises the steps:
B () compound 6 and methylating reagent react and prepare compound 7,
C () is prepared Cabazitaxel by compound 7,
Wherein, the solvent used in step (b) is DMSO；Reaction temperature is 0-20 DEG C, preferably 0 DEG C；The basic species used
Matter is sodium hydride.
The solvent used in step (c) is HCl/ ethanol；Reaction temperature is-10-10 DEG C, preferably-2-5 DEG C.
Further aspect of the present invention provides a kind of method preparing Cabazitaxel, comprises the steps:
(1) 10-DAB is that raw material reacts with silylating reagent, prepares formula III compound,
(2) formula III compound reacts with methylating reagent, prepares formula IV compound,
(3) formula IV compound and Formula II compound carry out condensation reaction, prepare Formula V compound,
(4) Formula V compound is taken off silylation protection group and is prepared compound 6,
(5) compound 6 and methylating reagent react and prepare compound 7,
(6) Cabazitaxel is prepared by compound 7,
Wherein, R1Selected from silylation, preferably TMS, triethyl silyl, tri isopropyl silane base, the tert-butyl group
Dimethylsilyl, tert-butyldiphenylsilanyl, more preferably triethyl silyl.
The silylating reagent used in step (1) is selected from trim,ethylchlorosilane, chlorotriethyl silane, triisopropyl chlorine silicon
Alkane, tert-butyl chloro-silicane, tert-butyl diphenyl chlorosilane etc., preferably chlorotriethyl silane.
The solvent used in step (1) is polar solvent, selected from DMF, pyridine, acetone or acetonitrile etc., preferably DMF or pyrrole
Pyridine.
Reaction temperature in step (1) is 0-20 DEG C, preferably 0 DEG C.
The reaction of step (1) is carried out in the basic conditions, and alkali is selected from triethylamine, pyridine or imidazoles etc., prioritizing selection imidazoles
Or pyridine.
In a specific embodiment of the present invention, the silylating reagent used in step (1) is chlorotriethyl silane,
The solvent used is pyridine, and reaction temperature is 0 DEG C.
In the another embodiment of the present invention, the silylating reagent used in step (1) is triethylchloro-silicane
Alkane, the solvent of use is DMF, and alkali is imidazoles, and reaction temperature is 0 DEG C.
The methylating reagent used in step (2) is selected from iodomethane, dimethyl sulfate, fluoromethane borate etc., preferably iodine
Methane.
The reaction of step (2) is carried out in the presence of a basic, alkaline matter selected from hydrofining, sodium hydride, LiHMDS,
NaHMDS, KHMDS etc., preferably LiHMDS.
In step (2), reaction dissolvent is selected from DMF, HMPA, oxolane etc., preferably oxolane.
In step (2), reaction temperature is-40-0 DEG C, preferably 0 DEG C.
In one detailed description of the invention of the present invention, the methylating reagent used in step (2) is iodomethane, use molten
Agent is oxolane, and alkaline matter is LiHMDS, and reaction temperature is 0 DEG C.
One or more in DCC, DPC, EDC I or DMAP of the condensing agent used in step (3), preferably DCC and
DMAP。
The mol ratio of DCC and DMAP used in step (3) is 2: 1.
In step (3), reaction dissolvent is selected from ethyl acetate, benzene, toluene, dichloromethane etc., preferably toluene or dichloromethane.
In step (3), reaction temperature is 25-80 DEG C, preferably 25 DEG C.
In one detailed description of the invention of the present invention, the condensing agent used in step (3) is DCC and DMAP, use molten
Agent is toluene, and reaction temperature is 25 DEG C.
The solvent used in step (4) is DCM；Reaction temperature is 0-20 DEG C；Reaction is entered in the presence of fluohydric acid gas-triethylamine
OK.
The solvent used in step (5) is DMSO；Reaction temperature is 0-20 DEG C, preferably 0 DEG C；Alkaline matter is sodium hydride.
The solvent used in step (6) is HC l/ ethanol；Reaction temperature is-10-10 DEG C, preferably-2-5 DEG C.
Offer midbody compound preparing Cabazitaxel of the present invention and preparation method thereof, by the intermediate system of the present invention
For the process of Cabazitaxel, the response time in each step is greatly shortened, and reaction yield is greatly improved, and greatly reduces kappa
The synthesis cost of his match.
Detailed description of the invention
The abbreviation used in the present invention has this area conventional sense, such as:
10-DAB is 10-deacetylation baccatin III；
DCC is dicyclohexylcarbodiimide；
DPC is 1,8-diaza-bicyclo [5,4,0] hendecene；
EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimine；
DMAP is DMAP；
DMF is DMF；
LiHMDS is LHMDS；
NaHMDS is sodium hexamethyldisilazide；
KHMDS is potassium hexamethyldisilazide；
HMPA is pregnancy phosphoric triamide；
DCM is dichloromethane；
DMSO is dimethyl sulfoxide；
Et is ethyl；
Bz is benzoyl；THF is oxolane；MeI is iodomethane；
PE/EA is petrol ether/ethyl acetate.
Following specific embodiment, its objective is to make those skilled in the art can be more clearly understood that and implement this
Bright.They should not be construed as limiting the scope of the present invention, and the simply exemplary illustration of the present invention and Typical Representative.This
Solvent, reagent and the raw material etc. that use in invention are commercially available prod.
Example 1: the preparation of compound 1
(1) preparation of compound 3
N2Under protection, 10-DAB (10.01g, 18.4mMol) is dissolved in 490ml DMF, is added thereto to imidazoles
(4.99g, 73.3mMol), ice bath is cooled to 0 DEG C, drips Et in system3SiCl (11.10g, 73.6mMol), drips and finishes, temperature
Maintaining 0 DEG C of reaction, after 2 hours, TLC detection raw material disappears.
First adding 100ml methyl tertiary butyl ether(MTBE) and 200ml water in backward system, temperature maintains about 0 DEG C, stirs 15 points
Clock, separates organic facies, and aqueous phase continues to use methyl tert-butyl ether extraction 2 times, merges organic facies, organic facies priority water and saturated food
Saline is respectively washed 2 times, and anhydrous magnesium sulfate is dried, and is concentrated under reduced pressure to give faint yellow solid.
By gained crude product with 60ml dichloromethane dissolve after cooling crystallization, sucking filtration, be dried to obtain white solid 10.93g.
After mother liquid obtained being evaporated, add 2ml dichloromethane dissolve after cooling crystallization, sucking filtration, be dried to obtain white solid
0.38g.Merge twice crystallized product, there are 11.31g compound 3, yield 93.4%.
1HNMR (400MHz, CDCl3) δ 0.53 (m, 6H), δ 0.95 (m, 9H), δ 1.08 (s, 3H), δ 1.18 (s, 3H), δ
1.58 (d, 1H), δ 1.74 (s, 3H), δ 1.90 (m, 1H), δ 2.01 (d, 1H), δ 2.10 (s, 3H), δ 2.28 (s, 2H), δ 2.29
(s, 3H), δ 2.50 (m, 1H), δ 3.95 (d, J=6.9Hz, 1H), δ 4.15 (d, J=8.2Hz, 1H), δ 4.23 (s, 1H), δ
(4.28 d, J=8.2Hz, 1H), δ 4.45 (dd, J=10.0,6.7Hz, 1H), δ 4.88 (m, 1H), δ 4.95 (d, 1H), δ 5.18
(s, 1H), δ 5.60 (d, 1H), δ 7.42 (t, 2H), δ 7.60 (t, 1H), δ 8.09 (d, 2H).
MS (FAB, DCM) m/z:for C35H50O10SiNa+.681.3。
Following methods can also be used to prepare compound 3:
N2Under protection, 10-DAB (4.00g, 7.35mMol) is dissolved in 320ml pyridine, at 0 DEG C, is slowly added dropwise Et3SiCl
(21.74g, 144.83mMol), drips and finishes, and is gradually increased to stirred overnight at room temperature, and TLC detection reaction is completely.
0 DEG C of downhill reaction liquid adds 100ml methyl tertiary butyl ether(MTBE) and saturated CuSO4Solution, after stirring 15min, separates
Organic facies, aqueous phase methyl tert-butyl ether extraction 2 times, merge organic facies, organic facies successively uses saturated CuSO4Solution and washing 3
Secondary, anhydrous magnesium sulfate is dried, and concentrating under reduced pressure must glue shape faint yellow solid.Gained dissolving crude product is cooled down after 25ml dichloromethane
Crystallize, sucking filtration, be dried to obtain 4.50g compound 3, yield 93%.
(2) preparation of compound 4
N2Under protection, compound 3 (10.50g, 15.95mMol) is dissolved in 290ml THF, is cooled to-40 DEG C, wherein
Dropping LiHMDS (20.75ml, 20.75mMol), drips and finishes, and stirs 30 minutes in-40 DEG C；Drip MeI the most wherein
(17.9ml, 287.2mMol)；Being gradually heating to 0 DEG C after dropping, after reacting 3 hours, HPLC detection raw material disappears.
Saturated NH is added in reaction system4Cl solution, after stirring 15 minutes, dilute, ethyl acetate extraction 3 times,
Merge organic facies；Organic facies priority water and saturated aqueous common salt wash 2 times, and anhydrous magnesium sulfate is dried.Removal of solvent under reduced pressure obtains
11.82g faint yellow solid.
Crude product is dissolved in cooling crystallization after 60ml dichloromethane, sucking filtration, is dried and to obtain 9.93g white-yellowish solid shape compound 4,
Yield 92.6%.
1HNMR (400MHz, CDCl3) δ 0.53 (m, 6H), δ 0.95 (m, 9H), δ 1.08 (s, 3H), δ 1.18 (s, 3H), δ
1.58 (d, 1H), δ 1.68 (s, 3H), δ 1.90 (m, 1H), δ 2.01 (d, 1H), δ 2.11 (s, 3H), 82.28 (s, 2H), δ 2.29
(s, 3H), δ 2.53 (m, 1H), δ 3.40 (s, 3H), δ 3.89 (d, J=6.9Hz, 1H), δ 4.15 (d, J=8.2Hz, 1H), δ
4.28 (d, J=8.2Hz, 1H), δ 4.45 (dd, J=10.0,6.7Hz, 1H), δ 4.95 (m, 3H), δ 5.60 (d, 1H), δ 7.42
(t, 2H), δ 7.60 (t, 1H), δ 8.09 (d, 2H).
MS (FAB, DCM) m/z:for C36H52O10SiNa+.695.3。
(3) preparation of compound 1
N2Under protection, by compound 4 (10.00g, 14.88mMol), compound 2 (7.72g, 19.34mMol) is in there-necked flask
In, it is added thereto to DCC (4.29g, 20.83mMol), DMAP (1.27g, 10.42mMol) and 60ml toluene；25 DEG C stirred
Night, TLC detection raw material disappear, filter, dilute, ethyl acetate extract 3 times, merge organic facies, organic facies priority water and
Saturated aqueous common salt washs 2 times, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure obtains white solid.
Gained crude product is obtained white solid 16.20g (eluant: PE/EA=3/1, V/V) through Flash column purification, by gained
White solid obtains 14.15g white solid compound 1, yield 90.3% through dichloromethane/normal hexane recrystallization.
1HNMR (400MHz, DMSO) δ 0.53 (m, 6H), δ 0.86 (m, 9H), δ 0.99 (m, 12H), δ 1.05 (s, 3H), δ
(1.45 s, 3H), δ 1.50 (s, 3H), δ 1.62 (m, 1H), δ 1.76 (s, 3H), δ 2.02 (m, 1H), δ 2.30 (m, 2H), δ 3.23
(s, 3H), δ 3.60 (d, 1H), δ 3.70 (s, 3H), δ 3.98 (m, 2H), δ 4.28 (dd, J=10.0,6.7Hz, 1H), δ 4.69
(m, 3H), δ 4.84 (d, 1H), δ 5.37 (m, 1H), δ 5.43 (d, 1H), δ 5.95 (m, 1H), δ 6.39 (s, 1H), δ 6.94 (d,
2H), δ 7.35 (d, 2H), δ 7.42 (t, 5H), δ 7.66 (m, 2H), δ 7.69 (m, 1H), δ 7.96 (d, 2H).
MS (FAB, DCM) m/z:for C58H75NO15Si Na+1076.5。
The preparation of example 2 Cabazitaxel
(1) preparation of compound 6
N2Under protection, compound 1 (5.00g, 4.75mMol) is dissolved in 50ml DCM, and drips wherein at 0 DEG C
Et3N.3HF (55.00ml, 341.91mMol), dripping and finish, temperature is gradually increased to 20 DEG C, and after stirring 2.5 hours, TLC detects raw material
Disappear, reactant liquor is dropped to the saturated NaHCO of 1L3In solution, separate organic facies after stirring 30min, aqueous phase 100ml DCM
Extract twice, merge organic facies；Organic facies priority water and saturated aqueous common salt are respectively washed 2 times, and anhydrous sodium sulfate is dried, and decompression removes
Solvent obtains 4.65g white solid.
Gained crude product is obtained 4.26g white solid compound 6 through dichloromethane/normal hexane recrystallization (1/4, V/V), receives
Rate 95.55%.
1HNMR (400MHz, DMSO) δ 0.99 (m, 12H), δ 1.05 (s, 3H), δ 1.45 (s, 3H), δ 1.50 (s, 3H), δ
1.62 (m, 1H), δ 1.74 (s, 3H), δ 2.02 (m, 1H), δ 2.24 (m, 2H), δ (3.23s, 3H), δ 3.58 (d, 1H), δ 3.76
(s, 3H), δ 3.98 (m, 3H), δ 4.63 (s, 1H), δ 4.70 (m, 1H), δ 4.80 (m, 2H), δ 4.93 (d, 1H), δ 5.33 (m,
1H), δ 5.43 (d, 1H), δ 5.97 (m, 1H), δ 6.39 (s, 1H), δ 6.94 (d, 2H), δ 7.35 (d, 2H), δ 7.42 (t, 5H), δ
7.66 (m, 2H), δ 7.69 (m, 1H), δ 7.96 (d, 2H).
MS (FAB, DCM) m/z:for C52H61NO15Na+962.4。
(2) preparation of compound 7
N2Under protection, compound 6 (1g, 1.065mmol) is dissolved in 4ml DMSO, and add MeI (2.1ml,
31.95mmol)；Ice bath is cooled to 0 DEG C, is dividedly in some parts NaH (4.29g, 20.83mmol), after charging, stirs 90 in 0 DEG C
After minute, TLC detection raw material disappears, and is added thereto to saturated ammonium chloride solution cancellation reaction, extracts 2 times by ethyl acetate, closes
And organic facies, washing with water, saturated sodium-chloride is washed, anhydrous sodium sulfate is dried, the white-yellowish solid of removal of solvent under reduced pressure.
Gained crude product obtains 820mg white solid compound 7, yield through column chromatography purification (eluant: PE: EA=2: 1)
80.8%.
MS (FAB, DCM) m/z:for C53H63NO15Na+976.40。
(3) preparation of Cabazitaxel
N2Under protection, take compound 7 (1.00g, 1,05mmol) and be dissolved in 12.5ml 0.1N HCl/EtOH；Keep temperature
It is stirred overnight at-2-5 DEG C, has a large amount of white to separate out.TLC detection raw material disappears, with saturated sodium bicarbonate regulation pH to neutral,
In cancellation course of reaction, temperature maintains between 0-5 DEG C all the time.Concentrating under reduced pressure removes part ethanol, dilutes with frozen water, by gained
Solid sucking filtration, is dried to obtain crude product 986mg.Gained crude product is obtained through column chromatography purification (eluant: DCM/MeOH=19: 1)
780mg white solid Cabazitaxel, yield 89%.
1HNMR (400MHz, CDCl3), δ 1.23 (s, 3H), δ 1.25 (s, 3H), δ 1.45 (s, 9H), δ 1.62 (m, 1H), δ
(1.74 s, 1H), δ 1.79 (s, 3H), δ 1.92and δ 2.83 (2mt, 1H), δ 1.95 (s, 3H), δ 2.43 (AB, 2H), δ 2.28
(s, 3H), δ 3.36 (s, 3H), δ 3.76 (s, 3H), δ 3.57 (mt, 1H), δ 3.88 (d, J=7,1H), δ 3.98 (dd, J=
10and 7,1H), δ 4.20and 4.33 (2d, 1H), δ 4.67 (mt, 1H), δ 4.88 (s, 1H), δ 4.93 (d, 1H), δ 5.26
(d, 1H), δ 5.37 (d, 1H), δ 5.43 (d, 1H), δ 6.39 (t, 1H), δ 7.42 (mt, 5H), δ 7.66 (t, 2H), δ 7.69 (t,
1H), δ 7.96 (d, 2H).
MS (FAB, DCM) m/z:for C45H57NO14Na+858.4。
Claims (1)
1. a preparation method for compound shown in Formula V, comprises the steps:
(1) 10-DAB is that raw material reacts with silylating reagent, prepares formula III compound,
(2) formula III compound reacts with methylating reagent, prepares formula IV compound,
(3) formula IV compound and formula II compound carry out condensation reaction, prepare the compound of formula V,
Wherein, R1Selected from triethyl silyl；
It is characterized in that, in step (1), the solvent of use is DMF, and reaction temperature is 0-20 DEG C, and reaction is entered in the basic conditions
OK, alkali is selected from imidazoles；
In step (2), the methylating reagent of use is iodomethane, and the solvent of use is oxolane, and alkali is LiHMDS, reaction temperature
Degree is 0 DEG C；
The condensing agent used in step (3) is DCC and DMAP, DCC and DMAP mol ratio is 2:1, and the solvent of use is toluene, instead
Answering temperature is 25 DEG C.
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| CN201110434548.3A CN103172654B (en) | 2011-12-22 | Bearing taxanes and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110434548.3A CN103172654B (en) | 2011-12-22 | Bearing taxanes and preparation method thereof |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5847170A (en) * | 1995-03-27 | 1998-12-08 | Rhone-Poulenc Rorer, S.A. | Taxoids, their preparation and pharmaceutical compositions containing them |
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5847170A (en) * | 1995-03-27 | 1998-12-08 | Rhone-Poulenc Rorer, S.A. | Taxoids, their preparation and pharmaceutical compositions containing them |
Non-Patent Citations (1)
| Title |
|---|
| A Chemoselective Approach to Functionalize the C-10 Position of 10-Deacetylbaccatin III . Synthesis and Biological Properties of Novel C-10 Taxol Analogues;Joydeep Kant et al.;《Tetrahedron Letters》;19941231;第35卷(第31期);5543-5546 * |
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