WO2014067207A1 - Cabazitaxel crystalline and preparation method therefor - Google Patents
Cabazitaxel crystalline and preparation method therefor Download PDFInfo
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- WO2014067207A1 WO2014067207A1 PCT/CN2012/086163 CN2012086163W WO2014067207A1 WO 2014067207 A1 WO2014067207 A1 WO 2014067207A1 CN 2012086163 W CN2012086163 W CN 2012086163W WO 2014067207 A1 WO2014067207 A1 WO 2014067207A1
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- white powder
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- hydroxy
- acetonitrile
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Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 229960001573 cabazitaxel Drugs 0.000 title abstract description 26
- 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 abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 57
- 239000000843 powder Substances 0.000 claims description 37
- 239000013078 crystal Substances 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 24
- 239000012153 distilled water Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 3
- 238000001144 powder X-ray diffraction data Methods 0.000 claims description 2
- 229960003668 docetaxel Drugs 0.000 abstract description 14
- 239000002904 solvent Substances 0.000 abstract description 13
- 239000012453 solvate Substances 0.000 abstract description 5
- 238000010586 diagram Methods 0.000 abstract description 3
- 238000000634 powder X-ray diffraction Methods 0.000 abstract description 2
- ZVAFCKLQJCZGAP-WDEREUQCSA-N (2r,3s)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H]([C@@H](O)C(O)=O)C1=CC=CC=C1 ZVAFCKLQJCZGAP-WDEREUQCSA-N 0.000 abstract 1
- 238000000967 suction filtration Methods 0.000 description 8
- 206010060862 Prostate cancer Diseases 0.000 description 6
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 6
- 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 5
- 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 5
- 229960004618 prednisone Drugs 0.000 description 5
- 230000008014 freezing Effects 0.000 description 4
- 238000007710 freezing Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical class CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- YWLXLRUDGLRYDR-YLPZXOTFSA-N 10-dab iii Chemical compound O([C@H]1[C@@H]2[C@](C([C@H](O)C3=C(C)[C@@H](O)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 YWLXLRUDGLRYDR-YLPZXOTFSA-N 0.000 description 1
- MGJMLMORVVDLIU-VHLOTGQHSA-N 183133-94-0 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](O)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 MGJMLMORVVDLIU-VHLOTGQHSA-N 0.000 description 1
- BWLBGMIXKSTLSX-UHFFFAOYSA-N 2-hydroxyisobutyric acid Chemical class CC(C)(O)C(O)=O BWLBGMIXKSTLSX-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010027452 Metastases to bone Diseases 0.000 description 1
- 229940122255 Microtubule inhibitor Drugs 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 102000001307 androgen receptors Human genes 0.000 description 1
- 108010080146 androgen receptors Proteins 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000010658 metastatic prostate carcinoma Diseases 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 231100000782 microtubule inhibitor Toxicity 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
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000011255 standard chemotherapy Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- -1 taxane compound Chemical class 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](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)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
Definitions
- the invention relates to the technical field of pharmacy, relates to a cabazitaxel crystal and a preparation method thereof, in particular to a cabazitaxel or 7, 10-dimethoxy docetaxel or (2R, 3S) -3- uncle T-oxycarbonylamino-2-hydroxy-3-phenylpropanoic acid 4-acetoxy-2 ⁇ -benzoyloxy-5 ⁇ , 20-epoxy-1-hydroxy-7 ⁇ , 10 ⁇ -dimethoxy- A crystalline form of 9-oxo-11-taxane-13 ⁇ -yl ester and a process for the preparation thereof.
- Background technique relates to the technical field of pharmacy, relates to a cabazitaxel crystal and a preparation method thereof, in particular to a cabazitaxel or 7, 10-dimethoxy docetaxel or (2R, 3S) -3- uncle T-oxycarbonylamino-2-hydroxy-3-phenylpropanoic acid 4-acetoxy-2 ⁇ -benzoyloxy-5 ⁇ ,
- Cabazitaxel [English name C a b az it aX el] is a taxane compound similar in structure to the anticancer drugs paclitaxel and docetaxel.
- Cabazitaxel is a microtubule inhibitor suitable for combination with prednisone for the treatment of patients with refractory metastatic prostate cancer who have been treated with docetaxel. It is approved in combination with prednisone to study the use of mHRPC patients.
- the docetaxel-containing regimen from this trial confirmed the use of cabazitaxel in combination with prednisone in patients with mHRPC, compared with the standard chemotherapy regimen of mitoxantrone and prednisone, statistically significantly reduced the risk of death.
- cabazitaxel is the first drug to treat advanced, anti-hormone-type prostate cancer when the use of the commonly used advanced prostate cancer drug docetaxel is ineffective or even worse.
- Cabazitaxel provides a new treatment for castration-resistant prostate cancer patients, which brings hope to prostate cancer patients, although only a modest benefit, but confirmed the effectiveness of prostate cancer immunotherapy.
- Treatment strategies for Phase III trials include stronger inhibition of androgen receptor signaling, regulation of novel signaling pathways in bone metastases (which affects more than 90% of late prostate patients), and enhanced anti-tumor immunity.
- the main process of synthesizing cabazitaxel is the patented synthesis process of Sanofi-Aventis, which uses 10-DABIII (10-deacetylated Baka T III) as raw material, and selects the hydroxyl groups at 7 and 10 positions. After methylation, 7,10-dimethoxy-10-DABIII is obtained, followed by various docetaxel side chains One of the condensation hydrolysiss gives the target product cabazitaxel (7, 10-dimethoxy docetaxel).
- the process is patented, the process is complicated, the reaction conditions are harsh, and the yield is low.
- the present invention relates to cabazitaxel or 7, 10-dimethoxy docetaxel or (2R,3S)-3-tert-t-oxycarbonylamino-2-hydroxy-3-phenylpropanoic acid 4-acetoxy Base-2 ⁇ -benzoyloxy-5 ⁇ , 20-epoxy-1-hydroxy-7 ⁇ , 10 ⁇ -dimethoxy-9-oxo-11-taxane-13 ⁇ -yl ester (English name:
- a crystal of cabazitaxel, 7, 10-dimethoxy docetaxel or (2R, 3S)-3-tert-T-oxycarbonylamino-2-hydroxy-3-benzene 4-Acetoxy-2 ⁇ -benzoyloxy-5 ⁇ , 20-epoxy-1-hydroxy-7 ⁇ , 10 ⁇ -dimethoxy-9-oxo-11-taxane-13 ⁇ - The crystalline form of the base ester.
- the acetonitrile solution is slowly added dropwise to the stirred frozen distilled water, and after stirring, stirring is continued, and a white powder is obtained by suction filtration;
- the white powder obtained in the step (3) is dried under reduced pressure at room temperature to obtain a target crystal form.
- the acetonitrile is acetonitrile heated to 30 °C.
- the distilled distilled water is distilled water frozen to 0 to 3'C.
- the stirring time is 30 to 40 min.
- the reduced pressure is a vacuum of 10 to 20 Pa.
- the drying time is 48 to 60 hours.
- the invention adopts acetonitrile as a solvent, and can effectively remove various residual solvents in the product, in particular, the use of 30'C acetonitrile is beneficial to the dissolution of the reaction intermediate white powder, thereby improving the reaction efficiency.
- the prepared cabazitaxel is a crystal form without an solvate, no crystal water and no solvent residue, and is produced as a product due to preparation under high vacuum room temperature. Small impact, good purity.
- Figure 1 is a graph of crystal PXED of an solvate free, crystal water free and free of any solvent.
- Figure 2 is a HPLC diagram of the crystals of the present invention without the solvate, without crystal water and without any solvent residue. detailed description
- the obtained white powder was depressurized (vacuum 10 ⁇ 20 Pa) and dried at room temperature for 48 h to obtain 37.4 g of a white powder.
- the obtained white powder was depressurized (vacuum 10 to 20 Pa ) and dried at room temperature for 48 h to obtain 75.1 g of a white powder.
- the present invention provides a cabazitaxel - 7, 10-dimethoxy docetaxel or (2E, 3S)-3-tert-T-oxycarbonylamino-2-hydroxy-3-phenylpropionic acid 4- Acetoxy-2 ⁇ -benzoyloxy-5 ⁇ , 20-epoxy-1-hydroxy-7 ⁇ , 10 ⁇ -dimethoxy-9-oxo-11-taxane-13 ⁇ - The unsolvate of the base ester, the crystal form without crystal water and without any solvent remaining.
- the melting point of the melting point is determined by differential scanning calorimetry (DSC), the melting point of which is 142 ° C, using powder-X-ray diffraction (PXED) method, the results are shown in Figure 1, which is shown by PXED diagram showing 4.3, 7.4, 8.6, 10.0, 11.0, 12.2, 12.6, 13.3, 13.6, 14.2, 15.0, 15.5, 16.4, 17.0, 18.1, 18.6, 20.2, 21.0, 21.6, 22. 22.8, 24.0, 24.6, 25.3, 25.8, 26.9, 28.0, Characteristic peaks of 29.4, 31.5, 32.0, 34.4, 35.5, 36.8 and 41.7° 2 ⁇ .
- the present invention uses acetonitrile as a solvent, and the residue in the solvent cannot be detected, and the content of the single impurity is not more than 0.05%.
- a method is applied in the US Patent No. 2005065138A1 as shown in FIG. Kappastat in the form of a acetonide Crystal, inventor in terms of solvent residue and cabazitaxel acetonide (US patent)
- Table 1 is the test result of the invention and the control index
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Epoxy Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosed is a cabazitaxel crystalline, 7,10-dimethoxy docetaxel or (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionic acid 4-acetoxy-2α-benzoxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxo-11-taxene-13α-yl ester in the form of crystalline without solvate and crystalline water, having the characteristic peaks shown at 4.3, 7.4, 8.6, 10.0, 11.0, 12.2, 2.6, 13.3, 13.6, 14.2, 15.0, 15.5, 16.4, 17.0, 18.1, 18.6, 20.2, 21.0, 21.6, 22.1, 22.8, 24.0, 24.6, 25.3, 25.8, 26.9, 28.0, 29.4, 31.5, 32.0, 34.4, 35.5, 36.8 and 41.7°2θ, characterized in a PXRD diagram. Also disclosed is a preparation method therefor. The product of the present invention is prepared at reduced pressure and at room temperature. The present invention has high yield and high purity, and does not have any solvent residue.
Description
说 明 书 Description
一种卡巴他赛晶体及其制备方法 Cabazitaxel crystal and preparation method thereof
技术领域 Technical field
本发明涉及药学的技术领域， 涉及一种卡巴他赛晶体及其制备方法， 具体涉及一种卡巴他赛或 7、 10-二甲氧基多西他赛或（2R，3S ) -3-叔 T氧羰 基胺基 -2-羟基 -3-苯基丙酸 4-乙酰氧基 -2α-苯甲酰氧基 -5β， 20-环氧 -1-羟基 -7β， 10β-二甲氧基 -9-氧代 -11-紫杉烯 -13α-基酯的结晶形式及其制备方法。 背景技术 The invention relates to the technical field of pharmacy, relates to a cabazitaxel crystal and a preparation method thereof, in particular to a cabazitaxel or 7, 10-dimethoxy docetaxel or (2R, 3S) -3- uncle T-oxycarbonylamino-2-hydroxy-3-phenylpropanoic acid 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1-hydroxy-7β, 10β-dimethoxy- A crystalline form of 9-oxo-11-taxane-13α-yl ester and a process for the preparation thereof. Background technique
卡巴他赛【英文名 CabazitaXel】是一种紫杉烷类化合物， 与抗癌药物 紫杉醇和多烯紫杉醇结构相似。 Cabazitaxel [English name C a b az it aX el] is a taxane compound similar in structure to the anticancer drugs paclitaxel and docetaxel.
卡巴他赛是一种微管抑制剂适用于与泼尼松联用治疗既往用含多烯紫 杉醇治疗方案激素难治转移性前列腺癌患者， 与泼尼松联用被批准， 研究 mHRPC患者既往用含多烯紫杉醇治疗方案，来自此试验结果证实采用卡巴 他赛与泼尼松联用对 mHRPC患者，与米托蒽醌和泼尼松标准剂量组成的阳 性化疗方案比较， 统计显著减低死亡风险。 Cabazitaxel is a microtubule inhibitor suitable for combination with prednisone for the treatment of patients with refractory metastatic prostate cancer who have been treated with docetaxel. It is approved in combination with prednisone to study the use of mHRPC patients. The docetaxel-containing regimen from this trial confirmed the use of cabazitaxel in combination with prednisone in patients with mHRPC, compared with the standard chemotherapy regimen of mitoxantrone and prednisone, statistically significantly reduced the risk of death.
2010年 6月 17日， 美国食品药品管理局 （FDA) 批准赛诺菲-安万特 公司的新药卡巴他赛 （cabazitaxel) 与泼尼松 （Prednisone) 联用治疗晚期 前列腺癌。 卡巴他赛 Cabazitaxel是第一个在使用常用晚期前列腺癌药物多 烯紫杉醇无效甚至病情加重时首选的治疗晚期、 抗激素型前列腺癌的药物。 卡巴他赛 Cabazitaxel为去势抵抗性前列腺癌患者提供了一种新型治疗， 这 给前列腺癌患者带来了希望， 虽然只获得了中度收益， 但证实了前列腺癌 免疫治疗的有效性。 进入 III期试验的治疗策略， 包括对雄激素受体信号更 强有力的抑制， 骨转移中新型信号通路的调节 （这会影响到 90%以上的晚 期前列腺患者） ， 以及加强抗肿瘤免疫。 On June 17, 2010, the US Food and Drug Administration (FDA) approved Sanofi-Aventis' new drug, cabazitaxel, in combination with prednisone for advanced prostate cancer. Cabazitaxel Cabazitaxel is the first drug to treat advanced, anti-hormone-type prostate cancer when the use of the commonly used advanced prostate cancer drug docetaxel is ineffective or even worse. Cabazitaxel provides a new treatment for castration-resistant prostate cancer patients, which brings hope to prostate cancer patients, although only a modest benefit, but confirmed the effectiveness of prostate cancer immunotherapy. Treatment strategies for Phase III trials include stronger inhibition of androgen receptor signaling, regulation of novel signaling pathways in bone metastases (which affects more than 90% of late prostate patients), and enhanced anti-tumor immunity.
目前合成卡巴他赛的主要工艺为赛诺菲-安万特公司的专利合成工艺， 采用 10-DABIII ( 10-脱乙酰基巴卡 T三） 为原料， 对其 7位和 10位上羟基 选择性甲基化后得到 7， 10-二甲氧基 -10-DABIII，然后与各种多西他赛侧链
之一缩合水解后得到目标产物卡巴他赛（7， 10-二甲氧基多西他赛） ， 该工 艺巳申请专利， 工艺复杂， 反应条件苛刻， 收率较低。 At present, the main process of synthesizing cabazitaxel is the patented synthesis process of Sanofi-Aventis, which uses 10-DABIII (10-deacetylated Baka T III) as raw material, and selects the hydroxyl groups at 7 and 10 positions. After methylation, 7,10-dimethoxy-10-DABIII is obtained, followed by various docetaxel side chains One of the condensation hydrolysiss gives the target product cabazitaxel (7, 10-dimethoxy docetaxel). The process is patented, the process is complicated, the reaction conditions are harsh, and the yield is low.
卡巴他赛存在多种晶体形式， 在美国专利 US2005065138A1 中申请了 一种丙酮合物形式的结晶物， 而中国专利 CN101918385A涉及了 5种无水 形式及一些相应的乙醇化物形式晶型， 但是专利中无水形式的晶型都是在 高温下得到， 这样对卡巴他赛的纯度会产生影响， 而且每一种晶型都有溶 剂残留， 这样对药品的安全性产生隐患。 发明内容 There are various crystal forms of cabazitaxel. In US Patent No. 2005065138A1, a crystal form in the form of a acetonate is applied, and Chinese patent CN101918385A relates to five anhydrous forms and some corresponding forms of the ethanolate form, but in the patent The anhydrous forms are obtained at high temperatures, which have an effect on the purity of the cabazitaxel, and each of the crystal forms has a solvent residue, which poses a potential hazard to the safety of the drug. Summary of the invention
本发明的目的在于提供一种卡巴他赛晶体， 且其无任何溶剂残留。 本发明的另一目的在于提供一种卡巴他赛晶体的制备方法。 It is an object of the present invention to provide a crystal of cabazitaxel without any solvent residue. Another object of the present invention is to provide a method for preparing a crystal of cabazitaxel.
本发明是关于卡巴他赛或 7、 10-二甲氧基多西他赛或（2R，3S ) -3-叔 T 氧羰基胺基 -2-羟基 -3-苯基丙酸 4-乙酰氧基 -2α-苯甲酰氧基 -5β， 20-环氧 -1- 羟基 -7β， 10β-二甲氧基 -9-氧代 -11 -紫杉烯 -13α-基酯 （英文名：
The present invention relates to cabazitaxel or 7, 10-dimethoxy docetaxel or (2R,3S)-3-tert-t-oxycarbonylamino-2-hydroxy-3-phenylpropanoic acid 4-acetoxy Base-2α-benzoyloxy-5β, 20-epoxy-1-hydroxy-7β, 10β-dimethoxy-9-oxo-11-taxane-13α-yl ester (English name:
(2R S>3-tert-buta?^cfflbQnykminO"2-hydrO>^-3-phenyl rO ffl )aie (2R S>3-tert-buta?^cfflbQnykminO"2-hydrO>^-3-phenyl rO ffl )aie
1 -hydiO>¾r-7p, 10p-dtmel oxy-9-oxo-5p,20-epo>¾ ax-l 1 -ene-2a!>4, 13 -triyl 4-acetate 2-benzoate 13-[(2R S>3-{[(terfbuta?¾¾ar Qnyl]amino}-2-hydrO>^-3-phenylprOpfflioate)的结晶形式及 其制备方法。 本发明所需要解决的技术问题， 可以通过以下技术方案来实现： 作为本发明的第一方面， 一种卡巴他赛晶体， 7、 10-二甲氧基多西他 赛或（2R，3S ) -3-叔 T氧羰基胺基 -2-羟基 -3-苯基丙酸 4-乙酰氧基 -2α-苯甲酰 氧基 -5β， 20-环氧 -1-羟基 -7β， 10β-二甲氧基 -9-氧代 -11 -紫杉烯 -13α-基酯的 晶体形式。 1 -hydiO>3⁄4r-7p, 10p-dtmel oxy-9-oxo-5p,20-epo>3⁄4 ax-l 1 -ene-2a !> 4, 13 -triyl 4-acetate 2-benzoate 13-[(2R The crystalline form of S>3-{[(terfbuta?3⁄43⁄4ar Qnyl]amino}-2-hydrO>^-3-phenylprOpfflioate) and the preparation method thereof. The technical problem to be solved by the present invention can be achieved by the following technical solutions: As a first aspect of the invention, a crystal of cabazitaxel, 7, 10-dimethoxy docetaxel or (2R, 3S)-3-tert-T-oxycarbonylamino-2-hydroxy-3-benzene 4-Acetoxy-2α-benzoyloxy-5β, 20-epoxy-1-hydroxy-7β, 10β-dimethoxy-9-oxo-11-taxane-13α- The crystalline form of the base ester.
其中， 7、 10-二甲氧基多西他赛或（2R，3S ) -3-叔 T氧羰基胺基 -2-羟基 -3-苯基丙酸 4-乙酰氧基 -2α-苯甲酰氧基 -5β， 20-环氧 -1 -羟基 -7β， 10β-二甲 氧基 -9-氧代 -11-紫杉烯 -13α-基酯的无溶剂合物、 无结晶水且无任何溶剂残 留的晶体形式， 其通过 PXRD图表征显示位于 4.3、 7.4、 8.6、 10.0、 11.0、
12.2、 12.6、 13.3、 13.6、 14.2、 15.0、 15.5、 16.4、 17.0、 18.1、 18.6、 20.2、 21.0、 21.6、 22.1、 22.8、 24.0、 24.6、 25.3、 25.8、 26.9、 28.0、 29.4、 31.5、 32.0、 34.4、 35.5、 36.8和 41.7°2Θ的特征峰， 如图 1所示。 作为本发明的第二方面，提供 7、 10-二甲氧基多西他赛或（2R，3S ) -3- 叔 T氧羰基胺基 -2-羟基 -3-苯基丙酸 4-乙酰氧基 -2α-苯甲酰氧基 -5β， 20-环氧 -1-羟基 -7β， 10β-二甲氧基 -9-氧代 -11-紫杉烯 -13α-基酯的无溶剂合物、 无结 晶水且无任何溶剂残留的晶体形式的制备方法， 其特征在于： Among them, 7, 10-dimethoxy docetaxel or (2R, 3S)-3-tert-oxycarbonylamino-2-hydroxy-3-phenylpropanoic acid 4-acetoxy-2α-benzoic acid Acetoxy-5β, 20-epoxy-1 -hydroxy-7β, 10β-dimethoxy-9-oxo-11-taxadiene-13α-yl ester, no solvate, no crystal water and no The crystal form of any solvent residue, which is characterized by PXRD pattern, is located at 4.3, 7.4, 8.6, 10.0, 11.0, 12.2, 12.6, 13.3, 13.6, 14.2, 15.0, 15.5, 16.4, 17.0, 18.1, 18.6, 20.2, 21.0, 21.6, 22.1, 22.8, 24.0, 24.6, 25.3, 25.8, 26.9, 28.0, 29.4, 31.5, 32.0, Characteristic peaks of 34.4, 35.5, 36.8 and 41.7 ° 2 ,, as shown in Figure 1. As a second aspect of the present invention, there is provided 7, 10-dimethoxy docetaxel or (2R,3S)-3-tert-T-oxycarbonylamino-2-hydroxy-3-phenylpropanoic acid 4-acetyl Solvent-free combination of oxy-2α-benzoyloxy-5β, 20-epoxy-1-hydroxy-7β, 10β-dimethoxy-9-oxo-11-taxane-13α-yl ester a preparation method of a crystal form having no crystal water and no solvent residue, characterized in that:
( 1 ) 将 7、 10-二甲氧基多西他赛或 （2R，3S ) -3-叔 T氧羰基胺基 -2-羟 基 -3-苯基丙酸 4-乙酰氧基 -2α-苯甲酰氧基 -5β， 20-环氧 -1-羟基 -7β， 10β-二 甲氧基 _9-氧代 -11-紫杉烯 -13α-基酯溶于 30'C乙腈中， 形成溶液； 再将所得 溶液搅拌下缓慢滴加至冷冻蒸馏水中， 滴加后继续搅拌， 抽滤得白色粉末; (1) 7,10-Dimethoxy docetaxel or (2R,3S)-3-tert-T-methoxycarbonylamino-2-hydroxy-3-phenylpropanoic acid 4-acetoxy-2α- Benzoyloxy-5β, 20-epoxy-1-hydroxy-7β, 10β-dimethoxy-9-oxo-11-taxadiene-13α-yl ester is dissolved in 30'C acetonitrile to form Solution; the resulting solution is slowly added dropwise to the frozen distilled water with stirring, and after stirring, stirring is continued, and a white powder is obtained by suction filtration;
(2) 将所得白色粉末减压室温干燥得白色粉末； (2) The obtained white powder is dried under reduced pressure at room temperature to obtain a white powder;
(3 ) 将步骤 （2) 所得的白色粉末溶于乙腈中； (3) dissolving the white powder obtained in the step (2) in acetonitrile;
再将乙腈溶液缓慢滴加至搅拌的冷冻蒸馏水中， 滴加后继续搅拌， 抽 滤得白色粉末； 以及 The acetonitrile solution is slowly added dropwise to the stirred frozen distilled water, and after stirring, stirring is continued, and a white powder is obtained by suction filtration;
(4) 将步骤 （3 ) 所得的白色粉末减压室温干燥得目标晶型。 (4) The white powder obtained in the step (3) is dried under reduced pressure at room temperature to obtain a target crystal form.
其中， 步骤 （1 ) 和 （3 ) 中， 所述乙腈为加热至 30'C的乙腈。 Wherein, in the steps (1) and (3), the acetonitrile is acetonitrile heated to 30 °C.
其中， 步骤 （1 ) 和 （3 ) 中， 所述冷冻蒸馏水为冷冻至 0〜3'C的蒸馏 水。 In the steps (1) and (3), the distilled distilled water is distilled water frozen to 0 to 3'C.
其中， 步骤 （1 ) 和 （3 ) 中， 所述搅拌时间为 30~40 min。 Wherein, in the steps (1) and (3), the stirring time is 30 to 40 min.
其中， 步骤 （2) 和 （4) 中， 所述减压为真空 10〜20 Pa。 Wherein, in steps (2) and (4), the reduced pressure is a vacuum of 10 to 20 Pa.
其中， 步骤 （2) 和 （4) 中， 所述干燥时间为 48~60h。 Wherein, in steps (2) and (4), the drying time is 48 to 60 hours.
本发明的有益效果： The beneficial effects of the invention:
本发明采用乙腈作为溶剂， 能高效的将产品中的各种残留溶剂除去， 尤其是采用 30'C乙腈有利于反应中间产物白色粉末的溶解，提高反应效率。 然后在 10〜20 Pa真空干燥后， 使得发明制备的卡巴他赛是无溶剂合物、无 结晶水且无任何溶剂残留的晶体形式，并且由于在高真空室温情况下制备， 对产品产生极小的影响， 纯度好。
附图说明 The invention adopts acetonitrile as a solvent, and can effectively remove various residual solvents in the product, in particular, the use of 30'C acetonitrile is beneficial to the dissolution of the reaction intermediate white powder, thereby improving the reaction efficiency. Then, after vacuum drying at 10 to 20 Pa, the prepared cabazitaxel is a crystal form without an solvate, no crystal water and no solvent residue, and is produced as a product due to preparation under high vacuum room temperature. Small impact, good purity. DRAWINGS
图 1为本发明的无溶剂合物、 无结晶水且无任何溶剂残留的晶体 PXED图。 图 2为本发明的无溶剂合物、 无结晶水且无任何溶剂残留的晶体 HPLC图。 具体实施方式 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph of crystal PXED of an solvate free, crystal water free and free of any solvent. Figure 2 is a HPLC diagram of the crystals of the present invention without the solvate, without crystal water and without any solvent residue. detailed description
以下结合具体实施例， 对本发明作进一步说明。 应理解， 以下实施例 仅用于说明本发明而非用于限定本发明的范围。 The invention will now be further described in conjunction with specific embodiments. It is to be understood that the following examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
实施例 1 Example 1
1、将卡巴他赛粉末 4 g溶于 100 ml乙腈（加热至 30'C )中， 再将所得 溶液缓慢滴加 （约 20 min) 至 1300 ml蒸馏水 （冷冻至 0〜3'C， 一定的搅 拌速度） 中， 滴加后继续搅拌 30 min, 抽滤得白色粉末。 1. Dissolve 4 g of Cabazitaxel powder in 100 ml of acetonitrile (heated to 30 ° C), then slowly add the solution (about 20 min) to 1300 ml of distilled water (freeze to 0~3'C, certain In the stirring speed), stirring was continued for 30 min after the dropwise addition, and a white powder was obtained by suction filtration.
2、所得白色粉末减压（真空 10〜20 Pa)室温干燥 48 h得 3.7 g白色粉 末。 2, the resulting white powder under reduced pressure (vacuum 10~20 P a) drying at room temperature 48 h to obtain 3.7 g of a white powder.
3、将操作 2 所得的白色粉末 3.7g溶于 100 ml乙腈（加热至 30'C )中， 再将所得溶液缓慢滴加 （约 20 min) 至 1300 ml蒸馏水 （冷冻至 0〜3'C， 一定的搅拌速度） 中， 滴加后继续搅拌 30 min， 抽滤得白色粉末。 3. Dissolve 3.7 g of the white powder obtained in operation 2 in 100 ml of acetonitrile (heated to 30 ° C), and slowly add the solution (about 20 min) to 1300 ml of distilled water (freeze to 0~3'C, In a certain stirring speed), stirring was continued for 30 min after the dropwise addition, and a white powder was obtained by suction filtration.
4、 所得白色粉末减压 （真空 10〜20 Pa) 室温干燥 48 h得 3. 5 g白色 粉末， 得率为 87. 5%， 纯度 99. 72 %。 实施例 2 The 5%, purity 99. 72%. The obtained white powder was decompressed (vacuum 10~20 Pa) and dried at room temperature for 48 h to obtain 3. 5 g of a white powder. The yield was 87.5%, and the purity was 99.72%. Example 2
1、将卡巴他赛粉末 40 g溶于 1 L乙腈（加热至 30'C )中， 再将所得溶 液搅拌下缓慢滴加 （约 2 h) 至 13 L蒸馏水 （冷冻至 0〜3'C， 一定的搅拌 速度） 中， 滴加后继续搅拌 30 min, 抽滤得白色粉末。 1. Dissolve 40 g of cabazitaxel powder in 1 L acetonitrile (heated to 30 ° C), and slowly add the solution (about 2 h) to 13 L of distilled water (freezing to 0~3'C, stirring). In a certain stirring speed), stirring was continued for 30 min after the dropwise addition, and a white powder was obtained by suction filtration.
2、 所得白色粉末减压 （真空 10〜20 Pa) 室温干燥 48 h得 37.4 g白色 粉末。 2. The obtained white powder was depressurized (vacuum 10~20 Pa) and dried at room temperature for 48 h to obtain 37.4 g of a white powder.
3、 将操作 2所得的白色粉末 37.4 g溶于 1 L乙腈 （加热至 30'C ) 中， 再将所得溶液搅拌下缓慢滴加（约 2 h)至 13 L蒸馏水（冷冻至 0〜3'C， 一 定的搅拌速度） 中， 滴加后继续搅拌 30 min, 抽滤得白色粉末。 3. 37.4 g of the white powder obtained in operation 2 was dissolved in 1 L of acetonitrile (heated to 30 ° C), and the resulting solution was slowly added dropwise (about 2 h) to 13 L of distilled water (freezing to 0 to 3'. C, a certain stirring speed), stirring was continued for 30 min after the dropwise addition, and a white powder was obtained by suction filtration.
4、所得粉末减压（真空 10〜20 Pa)室温干燥 48 h得 35.8 g白色粉末，
得率为 89.5%, 纯度为 99.70 % 实施例 3 4. The obtained powder is dried under reduced pressure (vacuum 10~20 P a ) at room temperature for 48 h to obtain 35.8 g of white powder. The yield is 89.5%, and the purity is 99.70%. Example 3
1、将卡巴他赛粉末 80 g溶于 2 L乙腈（加热至 30'C)中， 再将所得溶 液搅拌下缓慢滴加 （约 3 h) 至 26 L蒸馏水 （冷冻至 0〜3'C， 一定的搅拌 速度） 中， 滴加后继续搅拌 30 min, 抽滤得白色粉末。 1. Dissolve 80 g of Cabazitaxel powder in 2 L acetonitrile (heated to 30 ° C), and slowly add the solution (about 3 h) to 26 L of distilled water (freezing to 0~3'C, stirring, In a certain stirring speed), stirring was continued for 30 min after the dropwise addition, and a white powder was obtained by suction filtration.
2、 所得白色粉末减压 （真空 10〜20Pa) 室温干燥 48 h得 75.1 g白色 粉末。 2. The obtained white powder was depressurized (vacuum 10 to 20 Pa ) and dried at room temperature for 48 h to obtain 75.1 g of a white powder.
3、 将操作 2所得的白色粉末 75.1 g溶于 2 L乙腈 （加热至 30'C) 中， 再将所得溶液搅拌下缓慢滴加 （约 3 h) 至 26 L蒸馏水 （冷冻至 0〜3'C， 一定的搅拌速度） 中， 滴加后继续搅拌 30min， 抽滤得白色粉末。 3. 75.1 g of the white powder obtained in operation 2 was dissolved in 2 L of acetonitrile (heated to 30 ° C), and the resulting solution was slowly added dropwise (about 3 h) to 26 L of distilled water (freezing to 0 to 3'. C, a certain stirring speed), stirring was continued for 30 min after the dropwise addition, and a white powder was obtained by suction filtration.
4、 所得白色粉末减压 （真空 10〜20Pa) 室温干燥 48 h得 72.2 g白色 粉末， 得率为 90.3%, 纯度为 99.68%。 实施例 4 产品检测 4. The obtained white powder was depressurized (vacuum 10~20 Pa) and dried at room temperature for 48 h to obtain 72.2 g of white powder, the yield was 90.3%, and the purity was 99.68%. Example 4 Product Testing
本发明提供一种卡巴他赛—— 7、 10-二甲氧基多西他赛或（2E， 3S) -3- 叔 T氧羰基胺基 -2-羟基 -3-苯基丙酸 4-乙酰氧基 -2 α -苯甲酰氧基 -5 β， 20-环氧 -1-羟基 -7 β， 10 β-二甲氧基 -9-氧代 -11-紫杉烯 -13 α -基酯的无 溶剂合物、 无结晶水且无任何溶剂残留的晶体形式。 The present invention provides a cabazitaxel - 7, 10-dimethoxy docetaxel or (2E, 3S)-3-tert-T-oxycarbonylamino-2-hydroxy-3-phenylpropionic acid 4- Acetoxy-2 α -benzoyloxy-5 β, 20-epoxy-1-hydroxy-7 β, 10 β-dimethoxy-9-oxo-11-taxane-13 α - The unsolvate of the base ester, the crystal form without crystal water and without any solvent remaining.
其熔点采用差式扫描热法 （DSC) 检测熔点， 其熔点为 142'C， 采用粉 末一 X射线衍射 （PXED) 方法， 结果如图 1所示， 其通过 PXED图表征显示 位于 4.3、 7.4、 8.6, 10.0, 11.0, 12.2, 12.6, 13.3, 13.6, 14.2, 15.0, 15.5, 16.4, 17.0, 18.1, 18.6, 20.2, 21.0, 21.6, 22. 22.8, 24.0, 24.6、 25.3、 25.8、 26.9、 28.0、 29.4、 31.5、 32.0、 34.4、 35.5、 36.8 和 41.7° 2 Θ 的特征峰。 The melting point of the melting point is determined by differential scanning calorimetry (DSC), the melting point of which is 142 ° C, using powder-X-ray diffraction (PXED) method, the results are shown in Figure 1, which is shown by PXED diagram showing 4.3, 7.4, 8.6, 10.0, 11.0, 12.2, 12.6, 13.3, 13.6, 14.2, 15.0, 15.5, 16.4, 17.0, 18.1, 18.6, 20.2, 21.0, 21.6, 22. 22.8, 24.0, 24.6, 25.3, 25.8, 26.9, 28.0, Characteristic peaks of 29.4, 31.5, 32.0, 34.4, 35.5, 36.8 and 41.7° 2 Θ.
作为药品其各项指标都要求极为严格， 本发明采用乙腈作为溶剂， 在 溶剂残留是无法检出，在单个杂质含量上也是不超过 0.05%， 结果如图 2所 在美国专利 US2005065138A1中申请了一种卡巴他赛丙酮合物形式的结
晶物， 发明人在溶剂残留方面与卡巴他赛丙酮合物 （美国专利As a pharmaceutical, various indexes are required to be extremely strict. The present invention uses acetonitrile as a solvent, and the residue in the solvent cannot be detected, and the content of the single impurity is not more than 0.05%. As a result, a method is applied in the US Patent No. 2005065138A1 as shown in FIG. Kappastat in the form of a acetonide Crystal, inventor in terms of solvent residue and cabazitaxel acetonide (US patent)
US2005/0065138A1 ) 作了一个对比， 结果见表 1。 US2005/0065138A1) A comparison was made and the results are shown in Table 1.
表 1为本发明和对照指标检测结果 Table 1 is the test result of the invention and the control index
以上对本发明的具体实施方式进行了说明， 但本发明并不以此为限， 只要不脱离本发明的宗旨， 本发明还可以有各种变化。
The embodiments of the present invention have been described above, but the present invention is not limited thereto, and various modifications may be made without departing from the spirit and scope of the invention.
Claims
1、 7、 10-二甲氧基多西他赛或 （2R，3S ) -3-叔 T氧羰基胺基 -2-羟基 -3- 苯基丙酸 4-乙酰氧基 -2α-苯甲酰氧基 -5β， 20-环氧 -1 -轻基 -7β， 10β-二甲氧基 _9-氧代 -11 -紫杉烯 -13α-基酯的无溶剂合物、 无结晶水的晶体形式， 其通过 PXRD图表征显示位于 4.3、 7.4、 8.6、 10.0、 11.0、 12.2、 12.6、 13.3、 13.6、 14.2、 15.0、 15.5、 16.4、 17.0、 18.1、 18.6、 20.2, 21.0、 21.6、 22.1、 22.8、 24.0、 24.6、 25.3、 25.8、 26.9、 28.0、 29.4、 31.5、 32.0、 34.4、 35.5、 36.8 和 41.7°2Θ的特征峰。 1. 7. 10-Dimethoxydocetaxel or (2R, 3S)-3-tert. T-oxycarbonylamino-2-hydroxy-3-phenylpropionic acid 4-acetoxy-2α-benzyl Solvent-free, crystal water-free, acyloxy-5β, 20-epoxy-1-hydroxy-7β, 10β-dimethoxy-9-oxo-11-taxene-13α-yl ester Crystal form characterized by PXRD patterns showing locations at 4.3, 7.4, 8.6, 10.0, 11.0, 12.2, 12.6, 13.3, 13.6, 14.2, 15.0, 15.5, 16.4, 17.0, 18.1, 18.6, 20.2, 21.0, 21.6, 22.1. The characteristic peaks are 22.8, 24.0, 24.6, 25.3, 25.8, 26.9, 28.0, 29.4, 31.5, 32.0, 34.4, 35.5, 36.8 and 41.7°2Θ.
2、 根据权利要求 1所述的晶体形式的制备方法， 其特征在于： 2. The method for preparing a crystal form according to claim 1, characterized in that:
( 1 ) 将 7、 10-二甲氧基多西他赛或 （2R，3S ) -3-叔 T氧羰基胺基 -2-羟 基 -3-苯基丙酸 4-乙酰氧基 -2α-苯甲酰氧基 -5β， 20-环氧 -1-羟基 -7β， 10β-二 甲氧基 _9-氧代 -11-紫杉烯 -13α-基酯溶于 30'C乙腈中， 形成溶液； 再将所得 溶液搅拌下缓慢滴加至冷冻蒸馏水中， 滴加后继续搅拌， 抽滤得白色粉末; (1) 7, 10-dimethoxydocetaxel or (2R, 3S)-3-tert-Toxycarbonylamino-2-hydroxy-3-phenylpropionic acid 4-acetoxy-2α- Benzoyloxy-5β, 20-epoxy-1-hydroxy-7β, 10β-dimethoxy-9-oxo-11-taxene-13α-yl ester were dissolved in 30°C acetonitrile to form solution; then slowly drop the resulting solution into the frozen distilled water while stirring, continue stirring after the dropwise addition, and filter to obtain a white powder;
(2) 将所得白色粉末减压室温干燥得白色粉末； (2) Dry the obtained white powder under reduced pressure at room temperature to obtain white powder;
(3 ) 将步骤 （2) 所得的白色粉末溶于乙腈中； (3) Dissolve the white powder obtained in step (2) in acetonitrile;
再将乙腈溶液缓慢滴加至搅拌的冷冻蒸馏水中， 滴加后继续搅拌， 抽 滤得白色粉末； 以及 Then slowly add the acetonitrile solution dropwise to the stirred frozen distilled water, continue stirring after the dropwise addition, and filter with suction to obtain a white powder; and
(4) 将步骤 （3 ) 所得的白色粉末减压室温干燥得目标晶型。 (4) Dry the white powder obtained in step (3) under reduced pressure at room temperature to obtain the target crystal form.
3、 根据权利要求 2所述的制备方法， 其特征在于： 步骤 （1 ) 和 （3 ) 中， 所述乙腈为加热至 30'C的乙腈。 3. The preparation method according to claim 2, characterized in that: in steps (1) and (3), the acetonitrile is acetonitrile heated to 30°C.
4、 根据权利要求 2所述的制备方法， 其特征在于： 步骤 （1 ) 和 （3 ) 中， 所述冷冻蒸馏水为冷冻至 0〜3'C的蒸馏水。 4. The preparation method according to claim 2, characterized in that: in steps (1) and (3), the frozen distilled water is distilled water frozen to 0~3°C.
5、 根据权利要求 2所述的制备方法， 其特征在于： 步骤 （1 ) 和 （3 ) 中， 所述搅拌时间为 30~40 min。 5. The preparation method according to claim 2, characterized in that: in steps (1) and (3), the stirring time is 30~40 min.
6、 根据权利要求 2所述的制备方法， 其特征在于： 步骤 （2) 和 （4) 中， 所述减压为真空 10〜20 Pa。 6. The preparation method according to claim 2, characterized in that: in steps (2) and (4), the reduced pressure is vacuum 10~20 Pa.
7、 根据权利要求 2所述的制备方法， 其特征在于： 步骤 （2) 和 （4) 中， 所述干燥时间为 48~60h。
7. The preparation method according to claim 2, characterized in that: in steps (2) and (4), the drying time is 48 to 60 hours.
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| CN201210434983.0 | 2012-11-02 | ||
| CN201210434983.0A CN102898406B (en) | 2012-11-02 | 2012-11-02 | Cabazitaxel crystal and preparation method thereof |
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| US11413265B2 (en) | 2018-04-20 | 2022-08-16 | Zhuhai Beihai Biotech Co., Ltd. | Formulations and compositions of Cabazitaxel |
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| CN102746258B (en) * | 2012-07-25 | 2015-02-04 | 重庆泰濠制药有限公司 | Crystal forms of cabazitaxel and preparation method thereof |
| CN103450119B (en) * | 2013-09-24 | 2015-06-17 | 天津炜捷制药有限公司 | Cabazitaxel with crystal form W and method for preparing same |
| EP2865675A1 (en) * | 2013-10-23 | 2015-04-29 | INDENA S.p.A. | A crystalline anhydrous form of Cabazitaxel, process for the preparation and pharmaceutical compositions thereof |
| CN113429369B (en) * | 2021-07-23 | 2022-12-02 | 无锡紫杉药业有限公司 | Efficient cabazitaxel purification method |
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| CN102898406B (en) | 2014-12-03 |
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