CN102675257B - Cabazitaxel crystal and preparation method thereof - Google Patents
Cabazitaxel crystal and preparation method thereof Download PDFInfo
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- CN102675257B CN102675257B CN201210143771.7A CN201210143771A CN102675257B CN 102675257 B CN102675257 B CN 102675257B CN 201210143771 A CN201210143771 A CN 201210143771A CN 102675257 B CN102675257 B CN 102675257B
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Abstract
The invention relates to a cabazitaxel crystal which is solvent-free and non-crystallization water crystal form of 7, 10-dimethoxy docetaxel or (2R, 3S)-3-tert-butoxycarbonyl amino-2-hydroxyl-3- phenylpropionic acid 4-acetoxyl-2 alpha-benzoyloxy-5 beta, 20-epoxy-1-hydroxyl-7 beta, 10 beta- dimethoxy-9-oxo-11-taxadiene-13 alpha-ester; and the cabazitaxel crystal is shown to be positioned at 4.3, 7.1, 8.7, 10.2, 10.9, 12.2, 13.8, 15.2, 16.4, 17.0, 17.6, 18.3, 19.2, 19.6, 20.3, 21.2, 23.1, 24.7, 26.1, 27.3, 29.3, 31.9, 32.5 and 35.8 degrees 2 theta characteristic peak by powder X ray diffraction (PXRD). The invention also discloses a preparation method of the cabazitaxel crystal. The cabazitaxel crystal is prepared under the condition of reduced pressure at the room temperature, and is high in yield and good in purity.
Description
Technical field
The present invention relates to the technical field of pharmacy, relate to a kind of Cabazitaxel crystal and preparation method thereof, be specifically related to a kind of Cabazitaxel or 7,10-imethoxy docetaxel or (2R, 3S)-3-tertbutyloxycarbonyl amido-PLA 4-acetoxyl group-2 α-benzoyloxy-5 β, 20-epoxy-1-hydroxyl-7 β, crystallized form of 10 β-dimethoxy-9-oxo-11-Japanese yew alkene-13 α-Ji ester and preparation method thereof.
Background technology
Cabazitaxel [English name Cabazitaxel(JEVTANA)] be a kind of bearing taxanes, with anti-cancer medicine paclitaxel and Docetaxel structural similitude.
Cabazitaxel is that a kind of microtubule inhibitors is applicable to prednisone coupling treatment previously with containing Docetaxel treatment plan hormone refractory metastatic prostate cancer patient, go through with prednisone coupling, research mHRPC patient is previously with containing Docetaxel treatment plan, carrying out test-results since then confirms to adopt Cabazitaxel and prednisone coupling to mHRPC patient, with the positive chemotherapy regimen comparison of mitoxantrone and prednisone standard dose composition, statistically significant lowers mortality risk.
On June 17th, 2010, the new drug cabazitaxel(Jevtana of approval Sanofi-Aventis company of FDA (Food and Drug Adminstration) (FDA)) treat advanced prostate cancer with prednisone (Prednisone) coupling.Cabazitaxel Cabazitaxel is the treatment late period of first first-selection in the time using the conventional invalid even aggravation of advanced prostate cancer medicine Docetaxel, the medicine of hormone antagonist type prostate cancer.Cabazitaxel Cabazitaxel provides a kind of novel therapeutic for castration resistivity patients with prostate cancer, and this has brought hope to patients with prostate cancer, although only obtained moderate income, has confirmed the validity of prostate cancer immunotherapy.The therapeutic strategy that enters the test of III phase, comprises the more strong inhibition of androgen receptor signal, the adjusting (this can have influence on more than 90% prostate patient in late period) of novel signal path during bone shifts, and strengthen antineoplastic immune.
The main technique of at present synthetic Cabazitaxel is the patent synthesis technique of Sanofi-Aventis company; adopt 10-DABIII(10-deacetylation bar card fourth three) be raw material; above after hydroxyl selective methylations, obtain 7 to its 7 and 10; 10-dimethoxy-10-DABIII, then with after one of various docetaxel side chains condensation hydrolysis obtains target product Cabazitaxel (7,10-imethoxy docetaxel); this technique patent applied for; complex process, severe reaction conditions, yield is lower.
There is multiple crystalline form in Cabazitaxel, in US Patent No. 2005065138A1, apply for a kind of crystallisate of acetone compound form, and Chinese patent CN101918385A has related to 5 kinds of anhydrous forms and some corresponding ethylate form crystal formations, but in patent, the crystal formation of anhydrous form is all at high temperature to obtain, and can exert an influence like this to the purity of Cabazitaxel.
Summary of the invention
The object of the present invention is to provide a kind of Cabazitaxel crystal.
Another object of the present invention is to provide a kind of preparation method of Cabazitaxel crystal.
The invention relates to Cabazitaxel or 7,10-imethoxy docetaxel or (2R, 3S)-3-tertbutyloxycarbonyl amido-PLA 4-acetoxyl group-2 α-benzoyloxy-5 β, 20-epoxy-1-hydroxyl-7 β, crystallized form of 10 β-dimethoxy-9-oxo-11-Japanese yew alkene-13 α-Ji ester and preparation method thereof.
4-accetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,?10β-dimethoxy-9-oxotax-11-en-13α-yl?(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropanoate;?1-hydroxy-7β,10β-dimethoxy-9-oxo-5β,20-epoxytax-11-ene-2α,4,13α-triyl?4-acetate?2-benzoate?13-[(2R,3S)-3-{[(tertbutoxycarbonyl]amino}-2-hydroxy-3-phenylpropanoate
The technical problem that will solve required for the present invention, can be achieved through the following technical solutions:
As a first aspect of the present invention, a kind of Cabazitaxel crystal, 7,10-imethoxy docetaxel or (2R, 3S)-3-tertbutyloxycarbonyl amido-PLA 4-acetoxyl group-2 α-benzoyloxy-5 β, 20-epoxy-1-hydroxyl-7 β, the crystalline form of 10 β-dimethoxy-9-oxo-11-Japanese yew alkene-13 α-Ji ester.
Wherein, 7, 10-imethoxy docetaxel or (2R, 3S)-3-tertbutyloxycarbonyl amido-PLA 4-acetoxyl group-2 α-benzoyloxy-5 β, 20-epoxy-1-hydroxyl-7 β, the solvent-free compound of 10 β-dimethoxy-9-oxo-11-Japanese yew alkene-13 α-Ji ester, without the crystalline form of crystal water, it is schemed to characterize demonstration by PXRD and is positioned at 4.3, 7.1, 8.7, 10.2, 10.9, 12.2, 13.8, 15.2, 16.4, 17.0, 17.6, 18.3, 19.2, 19.6, 20.3, 21.2, 23.1, 24.7, 26.1, 27.3, 29.3, 31.9, the characteristic peak of 32.5 and 35.8 ° of 2 θ, as shown in Figure 1.
As a second aspect of the present invention, a kind of preparation method of Cabazitaxel crystal, 7,10-imethoxy docetaxel or (2R, 3S)-3-tertbutyloxycarbonyl amido-PLA 4-acetoxyl group-2 α-benzoyloxy-5 β, 20-epoxy-1-hydroxyl-7 β, the solvent-free compound of 10 β-dimethoxy-9-oxo-11-Japanese yew alkene-13 α-Ji ester, without the preparation method of the crystalline form of crystal water, it is characterized in that:
(1) by 7,10-imethoxy docetaxel or (2R, 3S)-3-tertbutyloxycarbonyl amido-PLA 4-acetoxyl group-2 α-benzoyloxy-5 β, 20-epoxy-1-hydroxyl-7 β, 10 β-dimethoxy-9-oxo-11-Japanese yew alkene-13 α-Ji ester is dissolved in freezing acetone, forms solution; To under gained solution stirring, slowly drop in freezing distilled water, after dripping, continue to stir, suction filtration obtains white powder;
(2) gained white powder decompression drying at room temperature is obtained to white powder;
(3) white powder of step (2) gained is dissolved in freezing acetone;
Acetone soln is slowly dropped in the described freezing distilled water of stirring again, after dripping, continue to stir, suction filtration obtains white powder; And
(4) the white powder decompression drying at room temperature of step (3) gained is obtained to target crystal formation.
Wherein, in step (1) and (3), described freezing acetone is to be refrigerated to the acetone of 0 DEG C.
Wherein, in step (1) and (3), described freezing distilled water is to be refrigerated to the distilled water of 0～3 DEG C.
Wherein, in step (1) and (3), described churning time is 50 min.
Wherein, in step (2) and (4), described decompression is vacuum 10～20 Pa.
Wherein, in step (2) and (4), be 48h described time of drying.
Beneficial effect of the present invention:
The invention provides a kind of solvent-free compound of Cabazitaxel, crystalline form without crystal water, under the tender feeling condition of underpressure chamber, prepare, yield is high, and purity is good.
Brief description of the drawings
Fig. 1 is solvent-free compound of the present invention, schemes without the PXRD of crystal water.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Should be understood that following examples are only for the present invention is described but not for limiting scope of the present invention.
Embodiment 1
1, Cabazitaxel powder 5 g are dissolved in 30 ml acetone (being refrigerated to 0 DEG C), then by slowly dripping (approximately 20 min) under gained solution stirring to 390 ml distilled water (being refrigerated to 0～3 DEG C), after dripping, continue to stir 30 min, suction filtration obtains white powder.
2, gained white powder decompression (vacuum 10～20 Pa) drying at room temperature 48 h obtain 4.4 g white powders.
3, white powder 4.5 g of operation 2 gained are dissolved in 30 ml acetone (being refrigerated to 0 DEG C), to under gained solution stirring, slowly drip (approximately 20 min) to 390 ml distilled water (being refrigerated to 0～3 DEG C) again, after dripping, continue to stir 30 min, suction filtration obtains white powder.
4, gained white powder decompression (vacuum 10～20 Pa) drying at room temperature 48 h obtain 4.1 g white powders, and yield is 82%wt, purity 99.75 % wt.
1, Cabazitaxel powder 10 g are dissolved in 60 ml acetone (being refrigerated to 0 DEG C), then by slowly dripping (approximately 30 min) under gained solution stirring to 780 ml distilled water (being refrigerated to 0～3 DEG C), after dripping, continue to stir 30 min, suction filtration obtains white powder.
2, gained white powder decompression (vacuum 10～20 Pa) drying at room temperature 48 h obtain 9 g white powders.
3, white powder 9 g of operation 2 gained are dissolved in 60 ml acetone (being refrigerated to 0 DEG C), to under gained solution stirring, slowly drip (approximately 30 min) to 780 ml distilled water (being refrigerated to 0～3 DEG C) again, after dripping, continue to stir 30 min, suction filtration obtains white powder.
4, gained powder decompression (vacuum 10～20 Pa) drying at room temperature 48 h obtain 8.5 g white powders, and yield is 85%wt, and purity is 99.80 % wt.
1, Cabazitaxel powder 100 g are dissolved in 600 ml acetone (being refrigerated to 0 DEG C), to under gained solution stirring, slowly drip (approximately 90 min) to 7800 ml distilled water (being refrigerated to 0～3 DEG C) again, after dripping, continue to stir 50 min, suction filtration obtains white powder.
2, gained white powder decompression (vacuum 10～20 Pa) drying at room temperature 48 h obtain 91 g white powders.
3, white powder 91 g of operation 2 gained are dissolved in 600 ml acetone (being refrigerated to 0 DEG C), to under gained solution stirring, slowly drip (approximately 90 min) to 7800 ml distilled water (being refrigerated to 0～3 DEG C) again, after dripping, continue to stir 50 min, suction filtration obtains white powder.
4, gained white powder decompression (vacuum 10～20 Pa) drying at room temperature 48 h obtain 88 g white powders, and yield is 88%wt, and purity is 99.78% wt.
Embodiment 4 products detect
The invention provides a kind of Cabazitaxel---7,10-imethoxy docetaxel or (2R, 3S)-3-tertbutyloxycarbonyl amido-PLA 4-acetoxyl group-2 α-benzoyloxy-5 β, 20-epoxy-1-hydroxyl-7 β, the solvent-free compound of 10 β-dimethoxy-9-oxo-11-Japanese yew alkene-13 α-Ji ester, without the crystalline form of crystal water
.
Its fusing point adopts poor formula scanning calorimeter method (DSC) to detect fusing point, its fusing point is 153.09 DEG C, adopt powder-X-ray diffraction (PXRD) method, as shown in Figure 1, it schemes sign by PXRD and shows the characteristic peak that is positioned at 4.3,7.1,8.7,10.2,10.9,12.2,13.8,15.2,16.4,17.0,17.6,18.3,19.2,19.6,20.3,21.2,23.1,24.7,26.1,27.3,29.3,31.9,32.5 and 35.8 ° of 2 θ result.
Above the specific embodiment of the present invention is illustrated, but the present invention is as limit, only otherwise depart from aim of the present invention, the present invention can also have various variations.
Claims (7)
1.7, the crystalline form of 10-imethoxy docetaxel, it is characterized in that: described crystalline form is 7, the crystalline form of the solvent-free compound of 10-imethoxy docetaxel, it is schemed sign by PXRD and shows the characteristic peak that is positioned at 4.3,7.1,8.7,10.2,10.9,12.2,13.8,15.2,16.4,17.0,17.6,18.3,19.2,19.6,20.3,21.2,23.1,24.7,26.1,27.3,29.3,31.9,32.5 and 35.8 ° of 2 θ.
2. the preparation method of crystalline form according to claim 1, is characterized in that: (1) is dissolved in 7,10-imethoxy docetaxel in freezing acetone, forms solution; To under gained solution stirring, slowly drop in freezing distilled water, after dripping, continue to stir, suction filtration obtains white powder;
(2) gained white powder decompression drying at room temperature is obtained to white powder;
(3) white powder of step (2) gained is dissolved in freezing acetone;
Acetone soln is slowly dropped in the freezing distilled water of stirring again, after dripping, continue to stir, suction filtration obtains white powder; And
(4) the white powder decompression drying at room temperature of step (3) gained is obtained to target crystalline form.
3. preparation method according to claim 2, is characterized in that: in step (1) and (3), described freezing acetone is to be refrigerated to the acetone of 0 DEG C.
4. preparation method according to claim 2, is characterized in that: in step (1) and (3), described freezing distilled water is to be refrigerated to the distilled water of 0～3 DEG C.
5. preparation method according to claim 2, is characterized in that: in step (3), described churning time is 50min.
6. preparation method according to claim 2, is characterized in that: in step (2) and (4), described decompression is vacuum 10～20Pa.
7. preparation method according to claim 2, is characterized in that:, in step (2) and (4), be 48h described time of drying.
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2621800T3 (en) | 2011-04-12 | 2017-07-05 | Teva Pharmaceuticals International Gmbh | Solid state forms of cabazitaxel and their preparation processes |
| US9394266B2 (en) | 2012-03-08 | 2016-07-19 | IVAX International GmbH | Solid state forms of cabazitaxel and processes for preparation thereof |
| CN103664836B (en) * | 2012-09-20 | 2016-04-20 | 齐鲁制药有限公司 | Crystal form A of 7 β, 10 β-dimethoxy docetaxel deuterated acetone compound and preparation method thereof |
| CN103058960B (en) * | 2012-12-12 | 2014-12-10 | 江苏奥赛康药业股份有限公司 | Cabazitaxel polymorphic form and preparation method thereof |
| EP2743264A1 (en) | 2012-12-13 | 2014-06-18 | INDENA S.p.A. | New crystalline form of cabazitaxel, process for the preparation and pharmaceutical compositions thereof |
| KR101429543B1 (en) | 2012-12-13 | 2014-08-14 | 주식회사 삼양바이오팜 | A novel crystal form of cabazitaxel and a method for preparing the same |
| EP2865674A1 (en) | 2013-10-23 | 2015-04-29 | INDENA S.p.A. | Crystalline solvate forms of Cabazitaxel |
| 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 |
| CN105367521A (en) * | 2014-08-21 | 2016-03-02 | 中国医学科学院药物研究所 | Cabazitaxel N4 crystal form substance, and preparation method, composition and use thereof |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1849311A (en) * | 2003-09-19 | 2006-10-18 | 安万特医药股份有限公司 | Acetone solvate of dimethoxy docetaxel and its process of preparation |
| CN101918385A (en) * | 2008-01-17 | 2010-12-15 | 安万特医药股份有限公司 | Crystalline forms of dimethoxy docetaxel and methods for preparing same |
| CN102060815A (en) * | 2010-12-24 | 2011-05-18 | 重庆泰濠制药有限公司 | Preparation method of taxanes compound |
| CN102285947A (en) * | 2011-06-17 | 2011-12-21 | 常州大学 | Method for synthesizing cabazitaxel |
| CN102311410A (en) * | 2011-09-29 | 2012-01-11 | 上海恒和医药科技有限公司 | Preparation method for cabazitaxel |
| 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 |
| CN102424672A (en) * | 2011-10-20 | 2012-04-25 | 江苏红豆杉生物科技有限公司 | Method for removing protective groups and preparing dimethoxy taxane compound |
| CN102503913A (en) * | 2011-10-20 | 2012-06-20 | 江苏红豆杉生物科技有限公司 | Preparation method for dimethoxy taxanes compound monocrystal directly used for X-ray single crystal diffraction analysis |
-
2012
- 2012-05-10 CN CN201210143771.7A patent/CN102675257B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1849311A (en) * | 2003-09-19 | 2006-10-18 | 安万特医药股份有限公司 | Acetone solvate of dimethoxy docetaxel and its process of preparation |
| CN101918385A (en) * | 2008-01-17 | 2010-12-15 | 安万特医药股份有限公司 | Crystalline forms of dimethoxy docetaxel and methods for preparing same |
| CN102060815A (en) * | 2010-12-24 | 2011-05-18 | 重庆泰濠制药有限公司 | Preparation method of taxanes compound |
| CN102285947A (en) * | 2011-06-17 | 2011-12-21 | 常州大学 | Method for synthesizing cabazitaxel |
| CN102311410A (en) * | 2011-09-29 | 2012-01-11 | 上海恒和医药科技有限公司 | Preparation method for cabazitaxel |
| 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 |
| CN102424672A (en) * | 2011-10-20 | 2012-04-25 | 江苏红豆杉生物科技有限公司 | Method for removing protective groups and preparing dimethoxy taxane compound |
| CN102503913A (en) * | 2011-10-20 | 2012-06-20 | 江苏红豆杉生物科技有限公司 | Preparation method for dimethoxy taxanes compound monocrystal directly used for X-ray single crystal diffraction analysis |
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Address after: 201715 Shanghai city Qingpu District Liantang Town Mao Dian Road No. 508 Patentee after: Shanghai King bio Pharmaceutical Co., Ltd. Address before: Liantang Town Qingpu District Shanghai city 201716 Zheng Xia Road 89 Lane No. 135 Patentee before: Jinhe Biological Technology Co., Ltd., Shanghai |