CN102952102B - Compound, preparation method thereof and application of compound in preparation of cabazitaxel - Google Patents
Compound, preparation method thereof and application of compound in preparation of cabazitaxel Download PDFInfo
- Publication number
- CN102952102B CN102952102B CN201210262692.8A CN201210262692A CN102952102B CN 102952102 B CN102952102 B CN 102952102B CN 201210262692 A CN201210262692 A CN 201210262692A CN 102952102 B CN102952102 B CN 102952102B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- preparation
- cabazitaxel
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 81
- 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 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 229960001573 cabazitaxel Drugs 0.000 title claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims description 150
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- -1 2,2,2-trichloro-ethoxycarbonyl Chemical group 0.000 claims description 8
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical group ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 239000002904 solvent Substances 0.000 abstract description 25
- 239000002994 raw material Substances 0.000 abstract description 16
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 14
- 239000000047 product Substances 0.000 abstract description 14
- 238000000034 method Methods 0.000 abstract description 8
- 239000012535 impurity Substances 0.000 abstract description 5
- 238000007086 side reaction Methods 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- OVMSOCFBDVBLFW-VHLOTGQHSA-N 5beta,20-epoxy-1,7beta,13alpha-trihydroxy-9-oxotax-11-ene-2alpha,4alpha,10beta-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 127
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 86
- 238000003381 deacetylation reaction Methods 0.000 description 65
- 239000000243 solution Substances 0.000 description 65
- 229930014667 baccatin III Natural products 0.000 description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 238000001035 drying Methods 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 24
- 238000005406 washing Methods 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- 239000003960 organic solvent Substances 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
- 238000000605 extraction Methods 0.000 description 20
- 239000012046 mixed solvent Substances 0.000 description 18
- 239000012043 crude product Substances 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 238000001953 recrystallisation Methods 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 238000010792 warming Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 239000010779 crude oil Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000009413 insulation Methods 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical class [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 7
- 239000003513 alkali Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 230000001035 methylating effect Effects 0.000 description 7
- 238000012805 post-processing Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000012362 glacial acetic acid Substances 0.000 description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
- 235000010755 mineral Nutrition 0.000 description 6
- 239000011707 mineral Substances 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 0 C=*=Cc1ccccc1 Chemical compound C=*=Cc1ccccc1 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 5
- 229910000105 potassium hydride Inorganic materials 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 206010060862 Prostate cancer Diseases 0.000 description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 238000012790 confirmation Methods 0.000 description 4
- 229960003668 docetaxel Drugs 0.000 description 4
- 229960004756 ethanol Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 102000029749 Microtubule Human genes 0.000 description 3
- 108091022875 Microtubule Proteins 0.000 description 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol 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 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 210000004688 microtubule Anatomy 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 3
- 229960004618 prednisone Drugs 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
- 238000013517 stratification Methods 0.000 description 3
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 125000003834 baccatin III group Chemical group 0.000 description 2
- 239000012964 benzotriazole Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052792 caesium Inorganic materials 0.000 description 2
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 208000010658 metastatic prostate carcinoma Diseases 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 231100000782 microtubule inhibitor Toxicity 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000004797 2,2,2-trichloroethoxy group Chemical group ClC(CO*)(Cl)Cl 0.000 description 1
- XXYYPZIGMITIFW-VYRBHSGPSA-N C[C@](C1)(C11C=CCCC1)OCC1=CC=CCC1 Chemical compound C[C@](C1)(C11C=CCCC1)OCC1=CC=CCC1 XXYYPZIGMITIFW-VYRBHSGPSA-N 0.000 description 1
- 206010061182 Genitourinary tract infection Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- UIQMVEYFGZJHCZ-SSTWWWIQSA-N Nalorphine 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
- 229940123237 Taxane Drugs 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000009261 endocrine therapy Methods 0.000 description 1
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000011354 first-line chemotherapy Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229940025735 jevtana Drugs 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 230000012106 negative regulation of microtubule depolymerization Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of pharmacy, particularly belongs to the field of the preparation of chemical drugs, and more particularly relates to a compound, a preparation method of the compound and the application of the compound in the preparation of cabazitaxel. In order to provide a cabazitaxel preparation method which is less in side reactions, high in product yield, less in byproducts, high in product quality, low in production cost, and suitable for the industrial production, the invention discloses a compound and a method for synthesizing cabazitaxel by the compound. The method disclosed by the invention is good in technical repeatability, less in solvent use level, lower in cost, and less in influence to operators and environment. According to the invention, the compound only needs to be refined by once or twice by normal reagent, so that the single impurity and the total impurity of midbodies and final products are less than 0.1% respectively, and the compound meets the quality requirement of bulk drug in ICH (international conference on harmonization) in the European union; and the compound can be taken as the raw material of cabazitaxel injection, and is very high in the value and the prospect of the industrial application.
Description
Technical field
The invention belongs to pharmacy field, particularly the preparation field of chemicals, more specifically relate to Cabazitaxel intermediate and preparation method thereof with its Cabazitaxel preparation in application.
Background technology
Prostate cancer is a kind of common male genitourinary system tumour, very high at European and American areas sickness rate, accounts for the second of male malignancy.According to statistics, the whole America in 2009 obtains new cancer about 760,000 example made a definite diagnosis, and wherein prostate cancer accounts for 25%.China's prostate-cancer incidence lower than America and Europe, but also in ascendant trend year by year, occupies the 3rd in male genitourinary tract infections malignant tumour.The treatment of prostate cancer, mainly contains expectant treatment, surgical operation therapy, radiotherapy, endocrine therapy, chemotherapy etc., formulates different treatment plans according to it by stages.Docetaxel associating prednisone is the First-line chemotherapy scheme of advanced androgen dependent/non-dependent metastatic prostate cancer, compared with combine prednisone scheme with mitoxantrone, the survival time extending patient with improve the quality of living on advantageously.For the patient that docetaxel curative effect is not good enough, Cabazitaxel likely becomes new therapeutic choice.
Cabazitaxel chemistry (2 α by name, 5 β, 7 β, 10 β, 13 α)-4-acetoxyl group-13-({ (2R, 3S)-3-[(tert-butoxycarbonyl) is amino]-2-hydroxyl-3-hydrocinnamoyl } oxygen)-1-hydroxyl-7,10-dimethoxy-9-oxo Japanese yew-5,20-epoxy group(ing)-11-alkene-2-benzoic ether;
Chemical structural formula:
Molecular formula: C
45h
57nO
14
Molecular weight: 835.93
Cabazitaxel (trade(brand)name: Jevtana), has another name called bi-methoxy docetaxel, belongs to taxane antitumor medicine, belong to microtubule inhibitors according to its mode of action, is to adopt the precursor of Ramulus et folium taxi cuspidatae extraction to be semi-syntheticly prepared from.U.S. FDA is in approval listing on June 17th, 2010, the Cabazitaxel injection of match Norfin, Inc exploitation is have approved through preferential examination and approval procedures, for combining Prednisone Therapy previously with the hormone refractory metastatic prostate cancer patient containing docetaxel treatment plan, be that it gets the Green Light in the world first specifically.
Cabazitaxel as a kind of microtubule inhibitors, by with tubulin binding, promote that microtubule dimer is assembled to microtubule, make microtubule stabilization by preventing polymerisation process from suppressing microtubule to decompose, blocks cellular is in G simultaneously
2with the M phase, thus the mitotic division of anticancer and propagation.
Typical Cabazitaxel synthetic route mainly contains two lines at present:
Route one (CN96192884.0) be with 10-deacetylate baccatin iii (hereinafter referred to as: 10-DAB) for starting raw material, first protect 7, the hydroxyl on 13, then 10 hydroxyls methylated.After 10 methylation reactions terminate; take off 7 again; silicoheptane base protection on 13; afterwards to 7 HMs; thus obtaining key intermediate 7 β, 10 β-dimethoxy-10-DAB, with this intermediate for raw material; carry out coupling with side-chain acid again, after purification, go protection to obtain Cabazitaxel.Its synthetic route is as follows:
route two (CN201110339593.0) take 10-DAB as starting raw material, first carries out coupling with side-chain acid, then slough 7,10 upper two protecting groups (2,2,2-tri-chloroethoxy base carbonyl).Pass through sodium hydride/methyl iodide afterwards to 7, the hydroxyl on 10 methylates, then open loop goes protection to obtain Cabazitaxel.Its synthetic route is as follows:
。
The step of synthesizing Cabazitaxel according to route one is many, and yield is low, and side reaction is more; And though it is short to synthesize the step of Cabazitaxel according to route two; but coupling carries out Deprotection and methylation reaction after crossing side-chain acid again; because side-chain acid group is comparatively large, structure is more complicated, and itself easily produces open loop; the side reactions such as racemization; the impurity produced is a lot, is difficult to purify by simple column purification, needs to carry out liquid phase preparation or repeatedly column purification; quantity of solvent uses very large, and after purification, yield is also very low.
Summary of the invention
The object of the present invention is to provide that a kind of side reaction is few, product yield is high, by product is few, quality product is high, and production cost is low, be applicable to suitability for industrialized production the preparation method of Cabazitaxel.
Technical scheme of the present invention is as follows:
First, the invention provides a kind of compound, it has following general structure:
Wherein, R is independently selected from methyl and substitutive derivative thereof;
R ' is selected from hydrogen base, methyl or 2,2,2-trichloro-ethoxycarbonyl respectively.
In the present invention, the selection of R ' has three kinds, is respectively 2,2,2-trichloro-ethoxycarbonyl, H, and methyl,
When to work as R ' be 2 Troc (i.e. 2,2,2-trichloro-ethoxycarbonyls), described general formula can be expressed as further:
。
When R ' is for H, described general formula can be expressed as further:
。
When R ' is for methyl, described general formula can be expressed as further:
Further, the present invention further discloses described R independently selected from methyl, phenyl or p-methoxyphenyl.
That is, preferred compound is chosen as in the present invention:
7,10-bis--O-(2,2,2-trichloro-ethoxycarbonyl)-13-O-ethanoyl-10-deacetylation baccatin III;
13-O-ethanoyl-10-deacetylation baccatin III;
7,10-bis--O-methoxyl group-13-O-ethanoyl-10-deacetylation baccatin III
7,10-bis--O-(2,2,2-trichloro-ethoxycarbonyl)-13-O-benzoyl-10-deacetylation baccatin III
13-O-benzoyl-10-deacetylation baccatin III
7,10-bis--O-methoxyl group-13-O-benzoyl-10-deacetylation baccatin III
7,10-bis--O-(2,2,2-trichloro-ethoxycarbonyl)-13-O-is to anisoyl-10-deacetylation baccatin III
13-O-is to anisoyl-10-deacetylation baccatin III
7,10-bis--O-methoxyl group-13-O-is to anisoyl-10-deacetylation baccatin III.
The present invention further discloses the preparation method of formula 3 compound, react as follows:
Described formula 2 compound is deposited at ambient at highly basic, and react the formula for preparing 3 compound with methylating reagent, wherein R is independently selected from methyl and substitutive derivative thereof, and described R is independently selected from methyl, phenyl or p-methoxyphenyl further.
Meanwhile, the preparation feedback that the present invention further discloses above-mentioned formula 2 compound is as follows:
Described formula 1 compound, in organic solvent system, adds activated zinc powder, stirs and obtains formula 2 compound, wherein Troc is 2,2,2-trichloro-ethoxycarbonyl, R is independently selected from methyl and substitutive derivative thereof, and described R is independently selected from methyl, phenyl or p-methoxyphenyl further.
Further, the preparation feedback that the invention discloses above-mentioned formula 1 compound is as follows:
7; 10-bis-(2; 2,2-trichloro-ethoxycarbonyl)-10-deacetylation baccatin III in organic solvent system, under the existence of organic bases; formula 1 compound is obtained with R-acyl chloride reaction; wherein Troc is 2,2,2-trichloro-ethoxycarbonyl; R is independently selected from methyl and substitutive derivative thereof, and described R is independently selected from methyl, phenyl or p-methoxyphenyl further.
Meanwhile, the present invention further discloses in the reaction of formula 2 preparation of compounds of formula 3 compound, preferably any one or a few condition following:
First in reaction flask, solvent is added under nitrogen protection, highly basic is added at temperature drop in reaction solution is to-70 DEG C ~-10 DEG C, add rear insulated and stirred reaction 15 ~ 30min, add the solution that formula 2 compound is dissolved in solvent formation again, add methylating reagent afterwards, control reacting liquid temperature-10 DEG C ~ 10 DEG C, stirring reaction, be warming up to 20 ~ 30 DEG C of insulation reaction after question response is stable, obtain formula 3 compound;
Described highly basic is selected from sodium hydride, potassium hydride KH, sodium methylate or sodium ethylate;
Described methylating reagent is selected from methyl iodide or methyl-sulfate;
Described solvent is anhydrous methylene chloride, anhydrous dimethyl formamide or anhydrous tetrahydro furan.
The invention also discloses in the reaction of formula 1 preparation of compounds of formula 2 compound, preferably any one or a few condition following:
Described formula 1 compound, in the organic solvent environment of 40 ~ 60 DEG C, adds activated zinc powder, insulated and stirred, obtains formula 2 compound;
Described organic solvent is the mixing solutions of methyl alcohol and glacial acetic acid.
Meanwhile, the invention also discloses in the preparation process of formula 1 compound, preferably any one or a few condition following:
Described 7,10-bis--O-(2,2,2-trichloro-ethoxycarbonyl)-10-deacetylation baccatin III in organic solvent, adds organic alkali agents and R-acyl chlorides, controls temperature in reaction solution and is no more than 10 DEG C of reactions, then be warming up to 80 ~ 100 DEG C of insulation reaction;
Described organic solvent is dry toluene or anhydrous dimethyl formamide;
Described organic bases is triethylamine, N, N-diisopropyl ethyl amine, N, N-diethyl ethylamine or N, N-diethylethanolamine.
Formula 3 compound described above can further for the preparation of formula 4 compound, and its reaction equation is shown below:
，
The definition of wherein said R is identical with the definition of R in above-claimed cpd, and namely R is independently selected from methyl and substitutive derivative thereof, and described R is independently selected from methyl, phenyl or p-methoxyphenyl further.
The embodiment of a kind of preparation formula 4 compound provided by the invention is: formula 3 compound in organic solvent; mineral alkali is added at temperature 30 ~ 40 DEG C in reaction solution; insulated and stirred is reacted; after reaction terminates; formula 4 compound 7,10-dimethoxy-10-deacetylation baccatin III is obtained through post-processing step.
Wherein said organic solvent is preferably methyl alcohol or ethanol; Described mineral alkali is preferably the common mineral alkalis such as Anhydrous potassium carbonate, Carbon Dioxide caesium, sodium hydroxide, potassium hydroxide.
On the basis of above compound, the present invention further discloses based on these compounds, prepare the method for Cabazitaxel, react as follows:
Described R is independently selected from methyl and substitutive derivative thereof, and described R is independently selected from methyl, phenyl or p-methoxyphenyl further, and Troc is 2,2,2-trichloro-ethoxycarbonyl, and described Ac is ethanoyl.
Above-mentioned formula 1, formula 2, formula 3 three compounds associate successively; the precursor compound 7 obtained is extracted from Ramulus et folium taxi cuspidatae; 10-bis--O-(2; 2; 2-trichloro-ethoxycarbonyl)-10-deacetylation baccatin III first synthetic compound 1; compound 1 deprotection obtains compound 2; compound 2 methylates further and forms compound 3; and by compound 3 slough further acyl group, with (4S; 5R)-2-(4-p-methoxy-phenyl)-4-phenyl-3,5-oxazolidine dicarboxylic acid-3-tert-butyl ester condensation, open loop, deprotection obtain Cabazitaxel.
Specifically, its synthesis step can be described as:
(1) 7; 10-bis--O-(2; 2,2-trichloro-ethoxycarbonyl)-10-deacetylation baccatin III in organic solvent, add organic alkali agents and R-acyl chlorides; control temperature in reaction solution and be no more than 10 DEG C of reactions; be warming up to 80 ~ 100 DEG C of insulation reaction again, then obtain formula 1 compound 7,10-bis--O-(2 through post-processing step; 2,2-trichloro-ethoxycarbonyl)-13-O-R-acyl group-10-deacetylation baccatin III.
(2) formula 1 compound in organic solvent, in reaction solution, add activated zinc powder at temperature 40 ~ 60 DEG C, and insulated and stirred is reacted, and obtains formula 2 compound 13-O-R-acyl group-10-deacetylation baccatin III after reaction terminates through post-processing step.
(3) first in reaction flask, solvent is added under nitrogen protection; highly basic is added at temperature drop in reaction solution is to-70 DEG C ~-10 DEG C; add rear insulated and stirred reaction 15 ~ 30min; add the solution that formula 2 compound and solvent are formed again; add methylating reagent afterwards; control reacting liquid temperature-10 DEG C ~ 10 DEG C; stirring reaction; 20 ~ 30 DEG C of insulation reaction are warming up to after question response is stable; formula 3 compound 7,10-dimethoxy-13-O-R-acyl group-10-deacetylation baccatin III is obtained through post-processing step after reaction terminates.
(4) formula 3 compound in organic solvent, in reaction solution, add mineral alkali at temperature 30 ~ 40 DEG C, and insulated and stirred is reacted, and after reaction terminates, obtains formula 4 compound 7,10-dimethoxy-10-deacetylation baccatin III through post-processing step.
(5) formula 4 compound is dissolved in organic solvent at temperature 25 ~ 35 DEG C in reaction solution, add (4S, 5R)-2-(4-p-methoxy-phenyl)-4-phenyl-3, the 5-oxazolidine dicarboxylic acid-3-tert-butyl ester, condensation reagent, auxiliary reagent, insulated and stirred is reacted, formula 5 compound (i.e. 3-tertbutyloxycarbonyl-2-(4-p-methoxy-phenyl)-4-phenyl-1 is obtained through post-processing step after reaction terminates, 3-oxazolidine-(2R, 4S, 5R)-5-carboxylic acid-4 α-acetoxyl-2 α-benzoyloxy-5 β, 20-epoxy-1 beta-hydroxy-9-oxygen-7 β, 10 β-dimethoxy-11-Japanese yew alkene-13 α ester).
(6) at temperature 20 ~ 30 DEG C, add formula 5 compound and one acid in organic solvent, insulated and stirred reaction, react after terminating and obtain finished product Cabazitaxel through post-processing step in reaction solution.
Wherein:
In step (1), optimum condition is: described organic solvent is preferably dry toluene or anhydrous dimethyl formamide; Described organic alkali agents is preferably the conventional organic basess such as triethylamine, N, N-diisopropyl ethyl amine, N, N-diethyl ethylamine or N, N-diethylethanolamine.
In step (2), optimum condition is: organic solvent is preferably the mixed solvent of methyl alcohol and glacial acetic acid.
In step (3), optimum condition is: described highly basic can be sodium hydride, potassium hydride KH, sodium methylate or sodium ethylate; Described methylating reagent can be methyl iodide or methyl-sulfate; Described solvent is preferably anhydrous methylene chloride, anhydrous dimethyl formamide or anhydrous tetrahydro furan.
In step (4), optimum condition is: organic solvent is preferably methyl alcohol or ethanol; Described mineral alkali is preferably the common mineral alkalis such as Anhydrous potassium carbonate, Carbon Dioxide caesium, sodium hydroxide, potassium hydroxide.
In step (5), optimum condition is: described organic solvent is preferably the one in dry toluene, dry methylene chloride or dry ethyl acetate; Described condensation reagent can be selected from N, N'-dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester or N, N ' the conventional condensation reagent such as-carbonyl dimidazoles, auxiliary reagent can be selected from DMAP, I-hydroxybenzotriazole.
In step (6), optimum condition is: described acid is preferably concentrated hydrochloric acid, trifluoromethanesulfonic acid, methylsulfonic acid or tosic acid.
The preparation method of Cabazitaxel provided by the invention, easy and simple to handle, aftertreatment is simple, good process repeatability, and solvent usage quantity is few, and cost is lower, to operator and environmental influence less.Simultaneously, preparation process side reaction is few, in intermediate and finished product, foreign matter content is low, conventional reagent only need be used to carry out 1 ~ 2 time refine, in midbody compound and finished product, single impurity and total impurities are all less than 0.1%, meet the specification of quality of European Union ICH bulk drug, as the raw material of Cabazitaxel injection liquid, value and the prospect of very high industrial application can be had.
Embodiment
The present invention is further illustrated below by embodiment.Should correct understanding: the method in embodiments of the invention is only for further illustrating the present invention, instead of limitation of the present invention, so, under method prerequisite of the present invention, all the scope of protection of present invention is belonged to simple modifications of the present invention.
In the present invention unless specifically stated otherwise, agents useful for same, instrument, equipment are commercial goods.
Use in the present invention 7; 10-bis-(2; 2; 2-trichloro-ethoxycarbonyl)-10-deacetylation baccatin III be the 10-deacetylation baccatin III (10-DAB) deriving from plant is raw material, prepares with reference to technical scheme disclosed in Chinese patent CN96192884.0, CN96192886.7.
The preparation of embodiment group 1 formula 1 compound and confirmation
Embodiment 1-1 7,10-bis--O-(2,2,2-trichloro-ethoxycarbonyl)-13-O-ethanoyl-10-deacetylation baccatin III
First in reaction flask, add 1L dry toluene; under mechanical stirring by 7; 10-bis--O-(2; 2; 2-trichloro-ethoxycarbonyl)-10-deacetylation baccatin III 100g (0.11mol) adds wherein; dissolve completely; in cooling reaction solution, temperature is to 0 DEG C; after adding triethylamine 62mL (0.44mol), continue to keep interior temperature 0 DEG C, be slowly added dropwise to Acetyl Chloride 98Min. 15.8mL (0.22mol); control temperature in reaction solution and be no more than 10 DEG C; drip insulated and stirred reaction 0.5h, then be warming up to 80 DEG C of insulation reaction 24h, have a large amount of solid to separate out.TLC detects and determines that reaction raw materials has reacted complete, slowly pours in saturated sodium bicarbonate aqueous solution, adds extraction into ethyl acetate aqueous phase, product-free residue in TLC point plate determination aqueous phase, organic phases washed with water and saturated common salt washing, anhydrous sodium sulfate drying.Filter, by filtrate evaporate to dryness, obtain oily matter.Crude product obtains 7,10-bis--O-(2,2,2-the trichloro-ethoxycarbonyl)-13-O-ethanoyl-10-deacetylation baccatin III of 94.3g through the mixed solvent recrystallization of methylene dichloride and sherwood oil, yield 90.1%.
ESI-MS(
m/z)：936.2(M-H)；
1H NMR (500 MHz, CDCl
3) δ(ppm) 1.172(s, 3H), 1.244(s, 3H), 1.847(s, 3H), 2.033(s, 3H), 2.216(s, 3H), 2.367(s, 3H),3.944(d,
J=7.0Hz, 1H), 4.163(d,
J=9.0Hz, 1H), 4.332(d,
J=9.0Hz, 1H), 4.613(d,
J=12.0Hz, 1H), 4.911(d,
J=12.0Hz, 1H), 4.799(s, 2H), 4.990(d,
J=9.0Hz, 1H), 5.593(m, 1H), 5.703(d,
J=7.0Hz, 1H), 6.217(t,
J=9.0Hz, 1H), 6.272(s, 1H), 7.511(d,
J=7.5Hz, 2H), 7.626(d,
J=7.0Hz, 1H), 8.083(d,
J=7.5Hz, 2H)。
Embodiment 1-2 7,10-bis--O-(2,2,2-trichloro-ethoxycarbonyl)-13-O-benzoyl-10-deacetylation baccatin III
First in reaction flask, add 500mL anhydrous dimethyl formamide; by 7; 10-bis--O-(2; 2; 2-trichloro-ethoxycarbonyl)-10-deacetylation baccatin III 50g (56mmol) dissolves in wherein; dissolve completely; in cooling reaction solution, temperature is to 0 DEG C; first add triethylamine 31mL (0.22mol); slowly be added dropwise to Benzoyl chloride 13.0mL (0.11mol) afterwards, control temperature in reaction solution and be no more than 10 DEG C, drip insulated and stirred reaction 0.5h; be warming up to 95 DEG C of insulation reaction 24h again, have a large amount of solid to separate out.React complete, slowly pour in saturated sodium bicarbonate aqueous solution, add extraction into ethyl acetate aqueous phase, organic phases washed with water and saturated common salt washing, anhydrous sodium sulfate drying.Filter, by filtrate evaporate to dryness, obtain oily matter.Crude product obtains 7,10-bis--O-(2,2,2-the trichloro-ethoxycarbonyl)-13-O-benzoyl-10-deacetylation baccatin III of 45.8g through the mixed solvent recrystallization of methylene dichloride and normal hexane, yield 82.0%.
ESI-MS(
m/z)：1000.1(M+H)；
1H NMR (500 MHz, CDCl
3) δ(ppm) 1.356(s, 3H), 1.361(s, 3H), 1.485(s, 3H), 1.942(s, 3H), 2.102(s, 3H), 2.165(m, 1H), 2.309(m, 1H), 2.311(dd,
J 1 =14.5Hz,
J 2 =6.1Hz, 1H), 2.316(dd,
J 1 =14.5Hz,
J 2 =7.9Hz, 1H), 2.676(d,
J=5.1Hz, 1H), 4.120(d,
J=16.5Hz, 1H), 4.166(dd,
J 1 =14.5Hz,
J 2 =4.5Hz, 1H), 4.573(s,2H), 4.584(s,2H), 5.027(m, 1H), 5.596(d,
J=5.1Hz, 1H), 5.704(m, 1H), 6.533(s, 1H), 7.458(m, 2H), 7.567(m, 2H), 7.604(m, 1H), 8.041(m, 2H), 8.167(m, 2H)。
Embodiment 1-3 7,10-bis--O-(2,2,2-trichloro-ethoxycarbonyl)-13-O-is to anisoyl-10-deacetylation baccatin III
350mL dry toluene is added in reaction flask; by 7; 10-bis--O-(2; 2; 2-trichloro-ethoxycarbonyl)-10-deacetylation baccatin III 35g (39mmol) dissolves in wherein; after dissolving completely; in cooling reaction solution, temperature is to 0 DEG C; first add triethylamine 22mL (0.16mol); slowly drip anisoyl chloride 10.6mL (78mmol) afterwards, control temperature in reaction solution and be no more than 10 DEG C, drip insulated and stirred reaction 0.5h; be warming up to 100 DEG C of insulation reaction 24h again, have a large amount of solid to separate out.React complete, slowly pour in saturated sodium bicarbonate aqueous solution, add extraction into ethyl acetate aqueous phase, organic phases washed with water and saturated common salt washing, anhydrous sodium sulfate drying.Filter, by filtrate evaporate to dryness, obtain sticky oil thing.Crude product obtains 7,10-bis--O-(2,2,2-the trichloro-ethoxycarbonyl)-13-O-of 37.1g to anisoyl-10-deacetylation baccatin III, yield 92.3% through the mixed solvent recrystallization of methylene dichloride and sherwood oil.
ESI-MS(
m/z)：1030.2(M+H)；
1H NMR (500 MHz, CDCl
3) δ(ppm) 1.317(s, 3H), 1.324(s, 3H), 1.456(s, 3H), 1.887(s, 3H), 2.134(s, 3H), 2.178(m, 1H), 2.306(dd,
J 1 =14.5Hz,
J 2 =4.2Hz, 1H), 2.315(dd,
J 1 =14.5Hz,
J 2 =7.9Hz, 1H), 2.331(dd,
J 1 =14.5Hz,
J 2 =6.1Hz, 1H), 2.687(d,
J=5.1Hz, 1H), 3.843(s, 3H), 4.056(d,
J=16.4Hz, 1H), 4.171(m, 2H), 4.556(s,2H), 4.579(s,2H), 5.120(m, 1H), 5.567(d,
J=5.1Hz, 1H), 5.679(m, 1H), 6.498(s, 1H), 7.058(m, 2H), 7.567(m, 2H), 7.604(m, 1H), 8.041(m, 2H), 8.167(m, 2H)。
The preparation of embodiment group 2 formula 2 compound and confirmation
Embodiment 2-1 13-O-ethanoyl-10-deacetylation baccatin III
1L anhydrous methanol and 110mL Glacial acetic acid is added in reaction flask, stir and heat up, 7 are added when temperature in reaction solution reaches 40 DEG C, 10-bis--O-(2, 2, 2-trichloro-ethoxycarbonyl)-13-O-ethanoyl-10-deacetylation baccatin III 90g (96mmol), after raw material dissolves completely, slowly add activated zinc powder 125g (1.92mol), add rear insulated and stirred reaction 2h, TLC point plate finds that raw material completes reaction, filter, filtrate pours crystallization in cold water into, filter, after filter cake is drained, with acetic acid ethyl dissolution, saturated sodium bicarbonate solution is used successively after filter cake dissolves completely, purified water and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, be concentrated into a small amount of solvent residue and have a large amount of solid to separate out, adding the 13-O-ethanoyl-10-deacetylation baccatin III that appropriate sherwood oil cooling crystallization obtains 51.4g, yield 91.3%.
ESI-MS(
m/z)：587.2(M+H)；
1H NMR (500 MHz, CDCl
3) δ(ppm) 1.117(s, 3H), 1.212 (s, 3H), 1.746(s, 3H), 1.863(m, 1H), 1.945(s, 3H), 2.230(s, 3H), 2.284(m, 1H), 2.322(s, 3H), 2.597(m, 1H), 3.951(d,
J=7.0Hz, 1H), 4.183(d,
J=9.0Hz, 1H), 4.265(m, 1H), 4.324(d,
J=9.0Hz, 1H), 4.988(d,
J=9.0Hz, 1H), 5.223(s, 1H), 5.674(d,
J=7.0Hz, 1H), 6.160(t,
J=9.0Hz, 1H), 7.482(d,
J=8.0Hz, 2H), 7.601(d,
J=7.0Hz, 1H), 8.073(d,
J=8.0Hz, 2H)。
Embodiment 2-2 13-O-benzoyl-10-deacetylation baccatin III
400mL anhydrous methanol and 60mL Glacial acetic acid is added in reaction flask; stir and heat up; 7 are added at temperature 40 DEG C in reaction solution; 10-bis--O-(2,2,2-trichloro-ethoxycarbonyl)-13-O-benzoyl-10-deacetylation baccatin III 45g (45mmol); after raw material dissolves completely; slowly add the zinc powder 29.3g (0.45mol) activated, add rear insulated and stirred reaction 2h, react substantially complete.Filter, filtrate directly pours crystallization in cold water into, and filter, filter cake ethyl acetate is dissolved completely.Organic phase saturated sodium bicarbonate solution, purified water and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, be concentrated into a small amount of solvent residue, have a large amount of solid to separate out, then add the 13-O-benzoyl-10-deacetylation baccatin III that normal hexane cooling crystallization obtains 24.7g, yield 84.6%.
ESI-MS(
m/z)：649.1(M+H)；
1H NMR (500 MHz, CDCl
3) δ(ppm) 1.335(s, 3H), 1.339(s, 3H), 1.864(s, 3H), 2.052(m, 1H), 2.077(m, 1H), 2.101(s, 3H), 2.304(dd,
J 1 =14.5Hz,
J 2 =6.0Hz, 1H), 2.311(dd,
J 1 =14.5Hz,
J 2 =7.9Hz, 1H), 2.665(d,
J=5.0Hz, 1H), 3.761(m, 1H), 4.117(s, 1H), 5.474(s, 1H), 5.601(d,
J=5.1Hz, 1H), 5.687(dd,
J 1 =7.9Hz,
J 2 =6.0Hz, 1H), 7.476(m, 2H), 7.567 (m, 2H), 7.583(m, 1H), 7.614(m, 1H), 8.028(m, 2H), 8.130(m, 1H)。
Embodiment 2-3 13-O-is to anisoyl-10-deacetylation baccatin III
320mL anhydrous methanol and 48mL Glacial acetic acid is added in reaction flask; stir and heat up; 7 are added at 40 DEG C; 10-bis--O-(2,2,2-trichloro-ethoxycarbonyl)-13-O-is to anisoyl-10-deacetylation baccatin III 36g (35mmol); after material dissolution; slowly add activated zinc powder 68.6g (1.05mol), add rear insulated and stirred reaction 1h, raw material primitive reaction is complete.Filter, filtrate directly pours crystallization in cold water into, and filter, filter cake ethyl acetate is dissolved completely.Organic phase saturated sodium bicarbonate solution, purified water and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, be concentrated into a small amount of solvent residue, have a large amount of solid to separate out, then add normal hexane cooling crystallization and obtain 19.8g 13-O-to anisoyl-10-deacetylation baccatin III, yield 83.5%.
ESI-MS(
m/z)：677.2(M-H)；
1H NMR (500 MHz, CDCl
3) δ(ppm) 1.337(s, 3H), 1.343(s, 3H), 1.351(s, 3H), 1.886(s, 3H), 2.064(m, 1H), 2.083(m, 1H), 2.123(s, 3H), 2.294 (dd,
J 1 =14.5Hz,
J 2 =6.0Hz, 1H), 2.302(dd,
J 1 =14.5Hz,
J 2 =7.9Hz, 1H), 2.651(d,
J=5.0Hz, 1H), 3.754(dd,
J 1 =4.2Hz,
J 2 =1.8Hz, 1H), 3.871(s, 3H),4.106(s, 1H), 4.127(s, 1H), 4.194(dd,
J 1 =4.5Hz,
J 2 =1.7Hz, 1H), 5.487(s, 1H), 5.598(d,
J=5.1Hz, 1H), 5.632(m, 1H), 7.102(m, 2H), 7.578(m, 2H), 7.596(m, 1H), 7.998(m, 2H), 8.207(m, 1H)。
The preparation of embodiment group 3 formula 3 compound and confirmation
Embodiment 3-1 7,10-dimethoxy-13-O-ethanoyl-10-deacetylation baccatin III
In reaction flask, add anhydrous methylene chloride 200mL under nitrogen protection, subcooling, at temperature drop in reaction solution is to-70 DEG C, adds potassium hydride KH 35.8g (30%, 0.27mol).13-O-ethanoyl-10-deacetylation baccatin III 50g (85mmol) is dissolved in 400mL anhydrous tetrahydro furan; slowly be added dropwise to the anhydrous methylene chloride mixing solutions of above-mentioned potassium hydride KH afterwards; control temperature in reaction solution and be no more than-50 DEG C, after adding, at-50 DEG C, insulated and stirred reacts 30min.In reaction solution, add methyl iodide 186mL (2.98mol), control temperature in reaction solution and be no more than-10 DEG C, add rear insulated and stirred reaction 2h.Slowly be warming up to 25 DEG C of reaction 24h reaction subsequently to terminate.The mixed aqueous solution then reaction solution slowly being poured into saturated ammonium chloride and ammoniacal liquor neutralizes, and uses dichloromethane extraction aqueous phase, organic phase purified water and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, be concentrated into dry, obtain oily matter.Be separated by gained crude product silicagel column, ethyl acetate and petroleum ether solvent system wash-out obtain blister 7,10-dimethoxy-13-O-ethanoyl-10-deacetylation baccatin III 29.1g, yield 55.5%.
ESI-MS(
m/z)：636.2(M+Na
+)；
1H NMR (500 MHz, CDCl
3) δ(ppm) 1.344(s, 3H), 1.354(s, 3H), 1.382(s, 3H), 1.862(m, 1H), 1.945(s, 3H), 2.043(m, 1H), 2.093(s, 3H), 2.093(s, 3H), 2.102(s, 3H), 2.218(m, 1H), 2.301(dd,
J 1 =14.5Hz,
J 2 =6.0Hz, 1H), 2.304(dd,
J 1 =14.5Hz,
J 2 =7.8Hz, 1H), 3.393(s, 3H), 3.398(s, 3H), 3.927(d,
J=4.2Hz, 1H), 4.119(d,
J=16.4Hz, 1H), 4.173(d,
J=16.4Hz, 1H), 4.183(dd,
J 1 =4.4Hz,
J 2 =1.7Hz, 1H), 5.434(s, 1H), 5.602(d,
J=5.0Hz, 1H), 5.665(dd,
J 1 =7.8Hz,
J 2 =6.1Hz, 1H), 7.567(m, 2H), 7.583(m, 1H), 8.130(m, 2H)。
Embodiment 3-2 7,10-dimethoxy-13-O-benzoyl-10-deacetylation baccatin III
Add anhydrous dimethyl formamide 48mL, subcooling in nitrogen protection downhill reaction bottle, at temperature drop in reaction solution is to-20 DEG C, adds sodium hydride 4.6g (60%, 0.27mol).13-O-benzoyl-10-deacetylation baccatin III 24g (37mmol) is dissolved in 72mL anhydrous dimethyl formamide; the complete molten clear anhydrous dimethyl formamide mixing solutions being slowly added dropwise to above-mentioned sodium hydride afterwards; control temperature in reaction solution and be no more than-5 DEG C, equality of temperature stirring reaction 30min.In reaction solution, add methyl iodide 69mL (1.11mol) again, control temperature in reaction solution and be no more than 0 DEG C, add rear insulated and stirred reaction 1h.Slowly be warming up to 30 DEG C of reaction 17h subsequently.Raw material primitive reaction is complete, then mixed aqueous solution reaction solution slowly being poured into saturated ammonium chloride and ammoniacal liquor neutralizes, and uses dichloromethane extraction aqueous phase, organic phase purified water and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, be concentrated into dry, obtain oily matter.Be separated by gained crude product silicagel column, ethyl acetate and petroleum ether solvent system wash-out obtain 7,10-dimethoxy-13-O-benzoyl-10-deacetylation baccatin III 10.2g, yield 40.8%.
ESI-MS(
m/z)：676.2(M)；
1H NMR (500 MHz, CDCl
3) δ(ppm) 1.349(s, 3H), 1.357(s, 3H), 1.391(s, 3H), 1.910(s, 3H), 2.056(m, 1H), 2.106(s, 3H), 2.227(m, 1H), 2.303(dd,
J 1 =14.5Hz,
J 2 =6.0Hz, 1H), 2.308(dd,
J 1 =14.5Hz,
J 2 =6.1Hz, 1H), 2.654(d,
J=5.0Hz, 1H), 3.417(s, 3H), 3.439(s, 3H),3.954(dd,
J 1 =4.2Hz,
J 2 =1.9Hz, 1H), 4.058(d,
J=16.4Hz, 1H), 4.167(d,
J=16.4Hz, 1H), 4.302(dd,
J 1 =4.4Hz,
J 2 =1.7Hz, 1H), 5.437(s, 1H), 5.609(d,
J=5.0Hz, 1H), 5.693(dd,
J 1 =7.8Hz,
J 2 =6.1Hz, 1H), 7.456(m, 2H), 7.578(m, 2H), 7.588(m, 1H), 8.016(m, 2H), 8.217(m, 2H)。
Embodiment 3-3 7,10-dimethoxy-13-O-is to anisoyl-10-deacetylation baccatin III
Add anhydrous tetrahydro furan 95mL, subcooling in nitrogen protection downhill reaction bottle, at temperature drop in reaction solution is to-10 DEG C, slowly adds sodium methylate solid 4.7g (87mmol).13-O-is dissolved in 95mL anhydrous tetrahydro furan to anisoyl-10-deacetylation baccatin III 19g (28mmol); until intermediate complete molten clear after be slowly added dropwise to the anhydrous tetrahydro furan mixing solutions of above-mentioned sodium methylate; control temperature in reaction solution and be no more than 0 DEG C, equality of temperature stirring reaction 30min.In reaction solution, add methyl-sulfate 26.5mL (0.28mol) again, control temperature in reaction solution and be no more than 10 DEG C, add rear insulated and stirred reaction 1h.Slowly be warming up to 30 DEG C of reaction 19h subsequently.The mixed aqueous solution after reacting completely, reaction solution slowly being poured into saturated ammonium chloride and ammoniacal liquor neutralizes, and uses dichloromethane extraction aqueous phase, organic phase purified water and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, be concentrated into dry, obtain oily matter.Be separated by gained crude product silicagel column, ethyl acetate and petroleum ether solvent system wash-out obtain 7,10-dimethoxy-13-O-to anisoyl-10-deacetylation baccatin III 6.4g, yield 32.3%.
ESI-MS(
m/z)：730.2(M+Na)；
1H NMR (500 MHz, CDCl
3) δ(ppm) 1.331(s, 3H), 1.347(s, 3H), 1.384(s, 3H), 1.988(s, 3H), 2.023(m, 1H), 2.145(s, 3H), 2.219(m, 1H), 2.303(dd,
J 1 =14.5Hz,
J 2 =7.8Hz, 1H), 2.307(dd,
J 1 =14.5Hz,
J 2 =6.1Hz, 1H), 2.667(d,
J=5.0Hz, 1H), 3.213(s, 3H), 3.224(s, 3H), 3.855(s, 3H),3.928(dd,
J 1 =4.2Hz,
J 2 =1.9Hz, 1H), 4.154(d,
J=16.4Hz, 1H), 4.203(d,
J=16.4Hz, 1H), 4.282(dd,
J 1 =4.4Hz,
J 2 =1.7Hz, 1H), 5.437(s, 1H), 5.605(d,
J=5.0Hz, 1H), 5.664(dd,
J 1 =7.8Hz,
J 2 =6.1Hz, 1H), 7.012(m, 2H), 7.544(m, 2H), 7.593(m, 1H), 8.102(m, 2H), 8.188(m, 2H)。
The preparation of embodiment group 4 formula 4 compound (7,10-dimethoxy-10-deacetylation baccatin III) and confirmation
Embodiment 4-1
7,10-dimethoxy-13-ethanoyl-10-deacetylation baccatin III 28g (46mmol) is dissolved in 280mL methyl alcohol, stirs and heats up.When adding Anhydrous potassium carbonate 12.6g (91mmol) at temperature 30 DEG C in reaction solution, insulated and stirred reaction 4h, starting raw material primitive reaction is complete.After reaction terminates, reaction solution is poured in cold water, add extraction into ethyl acetate aqueous phase, organic phase washed with water and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, by filtrate evaporate to dryness, obtain crude oil.Crude product obtains intermediate formula 4 compound (i.e. 7,10-dimethoxy-10-deacetylation baccatin IIIs) of 21.6g through acetone and sherwood oil mixed solvent recrystallization, yield 82.8%.
ESI-MS(
m/z)：573.2(M+H)；
1H NMR (500 MHz, CDCl
3) δ(ppm) 1.074(s, 3H), 1.166(s, 3H), 1.705(s, 3H), 1.744(m, 1H), 2.023(d,
J=6.5Hz, 1H), 2.111(s, 3H), 2.253(m, 2H), 2.291(s, 3H), 2.664(m, 1H), 3.341(s, 3H), 3.468(s, 3H), 3.867(m, 1H), 4.159 (d,
J=11.0Hz, 1H), 4.298(d,
J=11.0Hz, 1H), 4.840(s, 1H), 4.867(m, 1H),4.999(d,
J=10.5Hz, 1H), 5.579(d,
J=9.0Hz, 1H), 7.472(t,
J=9.8Hz, 2H), 7.599(t,
J=9.3Hz, 1H), 8.091(d,
J=9.0Hz, 1H)。
Embodiment 4-2
7,10-dimethoxy-13-O-benzoyl-10-deacetylation baccatin III 10g (15mmol) is dissolved in 100mL ethanol, stirs and heat up.When adding sodium hydroxide 0.88g (22mmol) at temperature 40 DEG C in reaction solution, insulated and stirred reaction 4h.Reaction terminates substantially, is poured into by reaction solution in cold water, adds extraction into ethyl acetate aqueous phase, organic phase washed with water and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, by filtrate evaporate to dryness, obtain crude oil.Crude product obtains intermediate formula 4 compound (i.e. 7,10-dimethoxy-10-deacetylation baccatin IIIs) of 6.5g through acetone/normal hexane mixed solvent recrystallization, yield 76.5%.
Embodiment 4-3
7,10-dimethoxy-13-O-is dissolved in 60mL methyl alcohol to anisoyl-10-deacetylation baccatin III 6g (8mmol), stirs and heat up.When adding Anhydrous potassium carbonate 1.8g (13mmol) at temperature 40 DEG C in reaction solution, insulated and stirred reaction 3h.Reaction terminates substantially, is poured into by reaction solution in cold water, adds extraction into ethyl acetate aqueous phase, organic phase washed with water and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, by filtrate evaporate to dryness, obtain crude oil.Crude product obtains the midbody product 4 of 3.4g through acetone/normal hexane mixed solvent recrystallization, yield 69.4%.
The preparation of embodiment 5 Cabazitaxel
(1) in reaction flask, 7 are added; 10-bis--O-(2; 2; 2-trichloro-ethoxycarbonyl)-10-deacetylation baccatin III and solvent; in reaction solution, add triethylamine at temperature 0 DEG C, be slowly added dropwise to R-acyl chlorides, control temperature in reaction solution and be no more than 10 DEG C; stirring reaction about 0.5h, then be warming up to 80 ~ 100 DEG C of insulation reaction.Slowly pour extraction in saturated sodium bicarbonate aqueous solution after reaction terminates into go out, add extraction into ethyl acetate three times, rear merging organic phase, wash with water and saturated common salt water washing, anhydrous sodium sulfate drying.Filter; by filtrate evaporate to dryness, the crude oil obtained obtains intermediate formula 1 compound (7,10-bis--O-(2 through the mixed solvent recrystallization of methylene dichloride and sherwood oil or normal hexane; 2,2-trichloro-ethoxycarbonyl)-13-O-R-acyl group-10-deacetylation baccatin III).Wherein solvent is dry toluene or anhydrous dimethyl formamide.
(2) in reaction flask, add formula 1 compound (7 of upper step, 10-bis--O-(2, 2, 2-trichloro-ethoxycarbonyl)-13-O-R-acyl group-10-deacetylation baccatin III) and solvent, slowly activated zinc powder is added at temperature 40 ~ 60 DEG C in reaction solution, add the reaction of rear insulated and stirred, reaction terminates rear filtration, filtrate pours crystallization in cold water into, filter, obtain filter cake acetic acid ethyl dissolution, adopt saturated sodium bicarbonate solution successively, anhydrous sodium sulfate drying after purified water and saturated common salt water washing, filter, be concentrated into a small amount of solvent, add sherwood oil or normal hexane cooling crystallization obtains intermediate formula 2 compound (13-O-R-acyl group-10-deacetylation baccatin III).Wherein solvent is the mixed solvent of methyl alcohol and glacial acetic acid.
(3) first in reaction flask, solvent is added under nitrogen protection; slowly highly basic is added at temperature drop in reaction solution is to-70 DEG C ~-10 DEG C; add rear insulated and stirred reaction 15 ~ 30min; slowly be added dropwise to the solution that formula 2 compound (13-O-R-acyl group-10-deacetylation baccatin III) that step obtains is formed with solvent again; add methylating reagent afterwards; control reacting liquid temperature-10 DEG C ~ 10 DEG C, stirring reaction 1 ~ 2h.20 ~ 30 DEG C of insulation reaction 12 ~ 24h are warming up to after question response is stable, to pour in the mixed aqueous solution of saturated ammonium chloride and ammoniacal liquor extraction after reaction terminates into go out, after dichloromethane extraction, adopt anhydrous sodium sulfate drying after purified water and saturated common salt water washing successively, filter, be concentrated into dry crude product.Gained crude product silica gel column chromatography is separated and obtains intermediate formula 3 compound (7,10-dimethoxy-13-O-R-acyl group-10-deacetylation baccatin III).Wherein solvent is anhydrous methylene chloride, anhydrous dimethyl formamide or anhydrous tetrahydro furan; Highly basic is sodium hydride, potassium hydride KH, sodium methylate or sodium ethylate; Methylating reagent is methyl iodide or methyl-sulfate.
(4) in reaction flask, add formula 3 compound (7 that upper step obtains; 10-dimethoxy-13-O-R-acyl group-10-deacetylation baccatin III) and organic solvent; in reaction solution, add Anhydrous potassium carbonate solid at temperature 30 ~ 40 DEG C, add rear insulated and stirred reaction 3 ~ 4h.After reaction terminates, pour in cold water, add extraction into ethyl acetate, organic phases washed with water and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, by filtrate evaporate to dryness, the crude oil obtained obtains intermediate formula 4 compound (7,10-dimethoxy-10-deacetylation baccatin III) through the mixed solvent recrystallization of acetone and sherwood oil or normal hexane.Wherein organic solvent is methyl alcohol or ethanol.
(5) first in reaction flask, organic solvent is added; formula 4 compound (7 is added at temperature 25 ~ 35 DEG C again in reaction solution; 10-dimethoxy-10-deacetylation baccatin III); complete after dissolving until it; add (4S, 5R)-2-(4-p-methoxy-phenyl)-4-phenyl-3, the 5-oxazolidine dicarboxylic acid-3-tert-butyl ester, N successively; N'-dicyclohexylcarbodiimide and DMAP, add rear insulated and stirred reaction 0.5 ~ 1h.Reaction terminates rear cold filtration, filtrate dilute acid wash, adds ethyl acetate strip aqueous, organic phase saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, by filtrate evaporate to dryness, the mixed solvent recrystallization of the crude oil ethyl acetate obtained and sherwood oil or normal hexane obtains intermediate formula 5 compound (3-tertbutyloxycarbonyl-2-(4-p-methoxy-phenyl)-4-phenyl-1,3-oxazolidine-(2R, 4S, 5R)-5-carboxylic acid-4 α-acetoxyl-2 α-benzoyloxy-5 β, 20-epoxy-1 beta-hydroxy-9-oxygen-7 β, 10 β-dimethoxy-11-Japanese yew alkene-13 α ester).Wherein organic solvent is the one in dry toluene, dry methylene chloride and dry ethyl acetate.
(6) in reaction flask, solvent is added, formula 5 compound (3-tertbutyloxycarbonyl-2-(4-p-methoxy-phenyl)-4-phenyl-1 is added successively at temperature 20 ~ 30 DEG C in reaction solution, 3-oxazolidine-(2R, 4S, 5R)-5-carboxylic acid-4 α-acetoxyl-2 α-benzoyloxy-5 β, 20-epoxy-1 beta-hydroxy-9-oxygen-7 β, 10 β-dimethoxy-11-Japanese yew alkene-13 α ester) and tosic acid, add rear insulated and stirred reaction 0.5 ~ 1h.Pour in cold sodium bicarbonate aqueous solution after reaction terminates, add extraction into ethyl acetate, organic phase washed with water and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, by filtrate evaporate to dryness, the mixed solvent recrystallization of the crude oil acetone obtained and sherwood oil or normal hexane obtains finished product Cabazitaxel.Wherein solvent is anhydrous methanol or dehydrated alcohol.
The preparation of embodiment 6 Cabazitaxel
In reaction flask, first add the dry toluene of 400mL; heat up and stir; formula 4 compound is added at temperature 35 DEG C in reaction solution; namely 7; 10-dimethoxy-10-deacetylation baccatin III 20g (35mmol); complete after dissolving until it; add (4S successively; 5R)-2-(4-p-methoxy-phenyl)-4-phenyl-3; 5-oxazolidine dicarboxylic acid-3-tert-butyl ester 28g (70mmol), N; N'-dicyclohexylcarbodiimide 21.6g (105mmol) and DMAP 4.3g (35mmol), adds rear insulated and stirred reaction 1h.TLC detects complete reaction, cold filtration, and filtrate is washed with dilute hydrochloric acid, stratification, adds ethyl acetate strip aqueous, and organic phase uses saturated sodium bicarbonate, water and saturated common salt water washing successively, anhydrous sodium sulfate drying.Filter, by filtrate evaporate to dryness, obtain oily matter.Crude product obtains midbody product formula 5 compound of 30.5g through ethyl acetate and sherwood oil mixed solvent recrystallization, yield 91.6%.
ESI-MS(
m/z)：976.2(M+Na
+)；
1H NMR (500 MHz, CDCl
3) δ(ppm) 1.348(s, 3H), 1.358(s, 3H), 1.384(s, 3H), 1.443(s, 9H), 1.914(s, 3H), 2.068(m, 1H), 2.102(s, 3H), 2.139(m, 1H), 2.259(dd,
J 1 =14.5Hz,
J 2 =1.7Hz, 1H), 2.446(dd,
J 1 =14.5Hz,
J 2 =7.5Hz, 1H), 2.722(d,
J=5.0Hz, 1H), 3.392(s, 3H), 3.418(s, 3H), 3.760(s, 3H), 3.861(dd,
J 1 =4.2Hz,
J 2 =1.9Hz, 1H), 4.108 (d,
J=16.5Hz, 1H), 4.280(d,
J=16.5Hz, 1H), 4.283(dd,
J 1 =4.4Hz,
J 2 =1.7Hz, 1H), 4.779(d,
J=1.8Hz, 1H), 4.834(d,
J=1.8Hz, 1H), 5.510(s, 1H), 5.644(dd,
J 1 =7.5Hz,
J 2 =1.7Hz, 1H), 5.706(d,
J=5.0Hz, 1H), 6.439(s, 1H), 6.968(m, 2H), 7.080(m, 2H), 7.260(m, 1H), 7.289(m, 2H), 7.398(m, 1H), 7.401(m, 1H), 7.523(m, 2H), 7.604(t,
J=7.5Hz, 1H), 8.185(m, 2H)。
Formula 5 compound 30g (31mmol) is dissolved in 300mL anhydrous methanol, heats up and stir, in reaction solution, at temperature 25 DEG C, add the tosic acid of 1.8g (10mmol), add rear equality of temperature stirring reaction 1h.TLC point plate confirms that raw material reacts completely, is poured in cold sodium bicarbonate aqueous solution by reaction solution, adds extraction into ethyl acetate, organic phase washed with water and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, by filtrate evaporate to dryness, obtain crude oil.Crude product obtains Cabazitaxel 16.3g, yield 62.0% through acetone and sherwood oil mixed solvent recrystallization.
ESI-MS(
m/z)：858.2(M+Na)；
1H NMR (500 MHz, CDCl
3) δ(ppm) 0.975(s, 3H), 1.012(s, 3H), 1.361(s, 9H), 1.477(m, 1H), 1.520(s, 3H), 1.714(m, 1H), 1.828(s, 3H), 1.868(m, 1H), 2.228(s, 3H), 2.647(m,1H), 3.218(s, 3H), 3.308(s, 3H), 3.608(d,
J=7.0Hz, 1H), 3.736(dd,
J 1 =10.0Hz,
J 2 =6.5Hz, 1H), 4.021(s, 2H), 4.338(d,
J=5.5Hz, 1H) 4.588(s, 1H), 4.707(s, 1H), 4.901 (t,
J=7.0Hz, 1H), 4.956(d,
J=9.5Hz, 1H), 5.377(d,
J=7.0Hz, 1H), 5.897(d,
J=8.5Hz, 2H), 7.211(d,
J=7.5Hz, 1H), 7.301(d,
J=7.0Hz, 2H), 7.380(t,
J=7.5Hz, 2H), 7.455(d,
J=9.0Hz, 1H), 7.625(t,
J=7.5Hz, 2H), 7.718(t,
J=7.0Hz, 1H), 7.965(d,
J=7.5Hz, 2H)。
The preparation of embodiment 7 Cabazitaxel
The dry methylene chloride of 60mL is added in reaction flask, heat up and stir, formula 4 compound is added at temperature 25 DEG C in reaction solution, namely 7, 10-dimethoxy-10-deacetylation baccatin III 6g (10mmol), complete after dissolving until it, add (4S successively, 5R)-2-(4-p-methoxy-phenyl)-4-phenyl-3, 5-oxazolidine dicarboxylic acid-3-tert-butyl ester 8.4g (21mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate 6.2g (32.3mmol) and I-hydroxybenzotriazole 1.5g (11.1mmol), add rear insulated and stirred reaction 0.5h.TLC detects complete reaction, cold filtration, and filtrate is washed with dilute hydrochloric acid, stratification, adds extraction into ethyl acetate aqueous phase, and organic phase uses saturated sodium bicarbonate, water and saturated common salt water washing successively, anhydrous sodium sulfate drying.Filter, by filtrate evaporate to dryness, obtain oily matter.Crude product obtains intermediate formula 5 compound of 9.5g through ethyl acetate and normal hexane mixed solvent recrystallization, yield 95.1%.
Formula 5 compound of 9g (9mmol) is dissolved in 90mL dehydrated alcohol, heats up and stir, in reaction solution, add tosic acid 1.6g (9mmol) at temperature 30 DEG C, add rear equality of temperature stirring reaction 0.5h.Raw material primitive reaction is complete, is poured in cold sodium bicarbonate aqueous solution by reaction solution, adds extraction into ethyl acetate, organic phase washed with water and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, by filtrate evaporate to dryness, obtain crude oil.Crude product obtains finished product Cabazitaxel 5.1g, product yield 64.7% through acetone and normal hexane mixed solvent recrystallization.
The preparation of embodiment 8 Cabazitaxel
The dry ethyl acetate of 30mL is added in reaction flask, heat up and stir, formula 4 compound is added at temperature 25 DEG C in reaction solution, namely 7, 10-dimethoxy-10-deacetylation baccatin III 3g (5mmol), complete after dissolving until it, add (4S successively, 5R)-2-(4-p-methoxy-phenyl)-4-phenyl-3, 5-oxazolidine dicarboxylic acid-3-tert-butyl ester 4.2g (10mmol), 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester 6.1g (16mmol) and DMAP 0.6g (5mmol), add rear insulated and stirred reaction 0.5h.TLC detects complete reaction, cold filtration, and filtrate is washed with dilute hydrochloric acid, stratification, adds ethyl acetate strip aqueous three times, merges organic phase.Organic phase uses saturated sodium bicarbonate, water and saturated common salt water washing successively, anhydrous sodium sulfate drying.Filter, by filtrate evaporate to dryness, obtain oily matter.Crude product obtains formula 5 compound of 4.5g through ethyl acetate and normal hexane mixed solvent recrystallization, yield 90.1%.
Formula 5 compound (4mmol) of 4g is dissolved in 40mL anhydrous methanol, heats up and stir, in reaction solution, add tosic acid 0.5g (3mmol) at temperature 20 DEG C, add rear equality of temperature stirring reaction 0.5h.Raw material primitive reaction is complete, is poured in cold sodium bicarbonate aqueous solution by reaction solution, adds extraction into ethyl acetate, organic phase washed with water and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, by filtrate evaporate to dryness, obtain crude oil.Crude product obtains Cabazitaxel 2.2g, product yield 62.9% through acetone and normal hexane mixed solvent recrystallization.
The above is the specific embodiment of the present invention, it should be pointed out that for those skilled in the art, can also make some improvements and modifications, and these improvements and modifications are also considered as protection scope of the present invention.
Claims (4)
1. a compound, is characterized in that for the compound shown in formula 1:
Wherein, R is selected from phenyl or p-methoxyphenyl.
2. a compound, is characterized in that for the compound shown in formula 2:
Wherein, R is selected from p-methoxyphenyl.
3. a compound, is characterized in that for the compound shown in formula 3:
Wherein, R is selected from phenyl or p-methoxyphenyl.
4. a preparation method for Cabazitaxel, is characterized in that reaction is as follows:
Described R is selected from methyl, phenyl or p-methoxyphenyl, and Troc is 2,2,2-trichloro-ethoxycarbonyl, and described Ac is ethanoyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210262692.8A CN102952102B (en) | 2012-07-27 | 2012-07-27 | Compound, preparation method thereof and application of compound in preparation of cabazitaxel |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210262692.8A CN102952102B (en) | 2012-07-27 | 2012-07-27 | Compound, preparation method thereof and application of compound in preparation of cabazitaxel |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102952102A CN102952102A (en) | 2013-03-06 |
| CN102952102B true CN102952102B (en) | 2015-04-22 |
Family
ID=47761546
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210262692.8A Expired - Fee Related CN102952102B (en) | 2012-07-27 | 2012-07-27 | Compound, preparation method thereof and application of compound in preparation of cabazitaxel |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102952102B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103333138A (en) * | 2013-07-22 | 2013-10-02 | 北京科莱博医药开发有限责任公司 | Novel Cabazitaxel crystal form, preparation method, application and pharmaceutical compositions thereof |
| CN106632158B (en) * | 2013-08-28 | 2018-11-06 | 江苏恒瑞医药股份有限公司 | The preparation method of 7 β, 10 β-dimethoxy -10- deacetylate Baccatine IIIs |
| CN104557798A (en) * | 2013-10-29 | 2015-04-29 | 神威药业集团有限公司 | Preparation method for dimethoxy docetaxel |
| CN115057833A (en) * | 2021-12-16 | 2022-09-16 | 上海健佑生物科技有限公司 | Synthetic route and intermediate compound of anticancer drug cabazitaxel |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102408397A (en) * | 2011-10-19 | 2012-04-11 | 上海贝美医药科技有限公司 | New taxane derivative and preparation method thereof |
| CN102417491A (en) * | 2011-10-31 | 2012-04-18 | 江苏红豆杉生物科技有限公司 | Method for preparing cabazitaxel by taking 10-deacetylate-baccatin III as raw material |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20140018917A (en) * | 2011-04-12 | 2014-02-13 | 플러스 케미칼스, 에스.에이. | Solid state forms of cabazitaxel and processes for preparation thereof |
| CN102675258B (en) * | 2012-05-25 | 2014-10-29 | 江苏红豆杉生物科技有限公司 | Novel taxane compound and preparation method thereof |
-
2012
- 2012-07-27 CN CN201210262692.8A patent/CN102952102B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102408397A (en) * | 2011-10-19 | 2012-04-11 | 上海贝美医药科技有限公司 | New taxane derivative and preparation method thereof |
| CN102417491A (en) * | 2011-10-31 | 2012-04-18 | 江苏红豆杉生物科技有限公司 | Method for preparing cabazitaxel by taking 10-deacetylate-baccatin III as raw material |
Non-Patent Citations (1)
| Title |
|---|
| Chemical studies of 10-deacetyl baccatin III: Hemisynthesis of taxol derivatives;Gueritte-Voegelein F et al;《Tetrahedron》;19861231;第42卷(第16期);4451页摘要及4452页图2，第4453页图4及4454页图5,第4457页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102952102A (en) | 2013-03-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102952102B (en) | Compound, preparation method thereof and application of compound in preparation of cabazitaxel | |
| JP5989987B2 (en) | Process for the preparation of taxoids from baccatin derivatives using Lewis acid catalysts | |
| CN106536506A (en) | Benzimidazole derivatives as erbb tyrosine kinase inhibitors for the treatment of cancer | |
| JP2001521493A (en) | 6-halo- or nitrate-substituted paclitaxel | |
| CA2152771C (en) | 7-o-ethers of taxane derivatives | |
| KR20160083021A (en) | Synthetic route to 2'-deoxy-2',2'-difluorotetrahydrouridines | |
| US20170114035A1 (en) | Method for Manufacturing Neuraminic Acid Derivatives | |
| CN105026384A (en) | Novel approach for synthesis of catechins | |
| CN112409183B (en) | Zanthoxylum bungeanum ketene and derivative thereof, and preparation method and application thereof | |
| CN115505019B (en) | 7-amide substituted estrogenic compounds, and preparation method and application thereof | |
| CN102212067B (en) | Garcinia derivative, method for preparing same and pharmaceutical application thereof | |
| WO2008093853A1 (en) | Solid of macrolide compound, method for production thereof, and pharmaceutical composition comprising the same | |
| CN103012329A (en) | Preparation method of taxol anticancer drugs Cabazitaxel XRP6258 | |
| CN104650109B (en) | Bearing taxanes | |
| AU776216B2 (en) | Semi-synthesis of paclitaxel using dialkyldichlorosilanes | |
| CN103012328B (en) | Method for preparing second-generation taxol anticancer drug Cabazitaxel | |
| CA2931291C (en) | Taxanes compounds, preparation method therefor, and uses thereof | |
| CN103025739A (en) | Preparation of tesetaxel and related compounds and corresponding synthesis intermediate | |
| CN103012330A (en) | Preparation method of taxol anticancer drugs XRP6258 | |
| CN104151271B (en) | Novel synthesis method of taxane antitumor drug cabazitaxel | |
| CN106674157A (en) | Novel cabazitaxel anhydrous compound and preparation method and crystal form thereof | |
| CN103450164B (en) | Geldanamycin derivatives as well as preparation methods and uses thereof | |
| CN106496263A (en) | The preparation method of hexahydro furyl furan 01 derivatives, its intermediate and preparation method thereof | |
| CN104892546B (en) | One class (2H) 1,4 benzo thiazides compounds and its preparation method and application | |
| CN101007795A (en) | Paclitaxel and docetaxel synthesis method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 211112 No. 699, Kejian Road, Nanjing Jiangning Science Park, Nanjing, Jiangsu Province Patentee after: JIANGSU AOSAIKANG PHARMACEUTICAL Co.,Ltd. Address before: 211112 No. 699, Kejian Road, Nanjing Jiangning Science Park, Nanjing, Jiangsu Province Patentee before: JIANGSU AOSAIKANG PHARMACEUTICAL Co.,Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150422 Termination date: 20210727 |