CN103664836A - Crystal form A of 7beta, 10beta-dimethoxy docetaxel deuterated acetone compound and preparation method of crystal form - Google Patents
Crystal form A of 7beta, 10beta-dimethoxy docetaxel deuterated acetone compound and preparation method of crystal form Download PDFInfo
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- 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
Abstract
The invention belongs to the field of medical chemical industry, and in particular relates to a compound crystal form A of a 7beta, 10beta-dimethoxy docetaxel deuterated acetone, and the preparation method of the crystal form A; the crystal form A of the 7beta, 10beta-dimethoxy docetaxel deuterated acetone compound has good stability, and relatively good solubility and high solution rate in the ethanol.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to a kind of 7 β, crystal form A of 10 β-dimethoxy docetaxel deuterated acetone compound and preparation method thereof; Described 7 β, the crystal form A of 10 β-dimethoxy docetaxel deuterated acetone compound has satisfactory stability, and in ethanol, has good solvability and dissolution rate.
Background technology
Prostate cancer is the modal malignant tumour of male reproductive system, occupies the second of male tumor, and annual more than 90 ten thousand the new cases that increase in the whole world, and nearly 260,000 people are dead.The sickness rate of prostate cancer increased with the age, and the medicine for the treatment of at present carcinoma of prostate mainly contains bicalutamide, docetaxel, rice and drags anthraquinone etc.Initial therapy suppresses to start mainly with male sex hormone; But with the development of the state of an illness, castration opposing is inevitable.
7 β, 10 β-dimethoxy docetaxel, its chemical name is 4-acetoxyl group-2 α-benzoyloxy-5 β, 20-epoxy group(ing)-1-hydroxyl-7 β, 10 β-dimethoxy-9-oxo yew-11-alkene-13 α-Ji (2R, 3S)-3-tert-butoxycarbonyl amino-PLA ester, has the chemical structure shown in formula I, is the new molecular design small molecules taxane anti-tumor medicament of the treatment prostate cancer of Sanofi-Aventis (Sanofi-aventis) company research and development.7 β, the mechanism of anticancer action of 10 β-dimethoxy docetaxel is similar to docetaxel with feature, belong to anti-microtubule class medicine, by with tubulin binding, promote microtubule dimer to be assembled into microtubule, by preventing that multimerization process from suppressing microtubule decomposition and making microtubule stable, retardance cell is in G2 and M phase simultaneously, thus the mitotic division of anticancer and propagation.7 β, 10 β-dimethoxy Taxotere not only also has activity to the responsive tumor line of docetaxel, and chemotherapy is comprised in the insensitive tumor model of docetaxel and still has activity.
U.S. FDA has been ratified 7 β in June, 2010, the listing of 10 β-dimethoxy docetaxel, and commodity are called Jevtana, are mainly used in prednisone coupling treatment previously with containing Docetaxel treatment plan hormone refractory metastatic prostate cancer patient.
At present, CN 1849311A discloses 7 β, acetone compound of 10 β-dimethoxy docetaxel and preparation method thereof; WO2012088433 discloses 7 β that heavy hydrogen replaces or fluorine replaces, 10 β-dimethoxy docetaxel compound, and WO2012088445 discloses based on 7 β, the higly branched chain polymerization prodrug conjugates of 10 β-dimethoxy docetaxel; Although based on 7 β, the various structure compounds that change of 10 β-dimethoxy docetaxel are disclosed more and more, 7 β, 10 β-dimethoxy docetaxel deuterated acetone compound and crystal formation thereof are not yet by bibliographical information.
Summary of the invention
For above-mentioned the deficiencies in the prior art, the invention provides a kind of 7 β, deuterated acetone compound crystal form A of 10 β-dimethoxy docetaxel and preparation method thereof; It should be noted that, deuterated acetone of the present invention refers to that in acetone molecules, hydrogen atom, entirely for the acetone of deuterium (D or 2H) atom, has CD
3(CO) CD
3molecular formula and
structural formula.The inventor surprisingly finds, 7 β, and some form of 10 β-dimethoxy docetaxel deuterated acetone compound, is the crystalline substance with favourable character.
First aspect present invention provides a kind of 7 β, the crystal form A of the deuterated acetone solvate of 10 β-dimethoxy docetaxel, described 7 β, in 10 β-dimethoxy docetaxel deuterated acetone compound, the content of deuterated acetone is massfraction 5.5%-7.5%, preferred 6.0%-7.0%, more preferably 6.5%-6.9%, most preferably 6.7%; Described 7 β, the crystal form A of the deuterated acetone compound of 10 β-dimethoxy docetaxel is used Cu-K α radiation, the X-ray powder diffraction representing with 2 θ angles is at 8.9 ± 0.2 °, 10.3 ± 0.2 °, 12.9 ± 0.2 °, 17.7 ± 0.2 °, 19.9 ± 0.2 °, located characteristic peak for 21.9 ± 0.2 °.
Further, described 7 β, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A, is used Cu-Ka radiation, the X-ray powder diffraction representing with 2 θ angles is also at 7.6 ± 0.2 °, and 8.0 ° ± 0.2 °, 12.7 ± 0.2 °, 13.6 ± 0.2 °, 14.5 ± 0.2 °, 15.1 ± 0.2 °, 15.9 ± 0.2 °, 16.7 ± 0.2 °, 17.1 ± 0.2 °, 18.3 ± 0.2 °, 20.5 ± 0.2 °, 21.2 ± 0.2 °, 22.3 ± 0.2 °, 23.1 ± 0.2 °, located characteristic peak for 24.0 ± 0.2 °.
Further, described 7 β, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A has X-ray powder diffraction as shown in Figure 1.
Contriver is to 7 β, and 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A carries out differential scanning calorimetric analysis (DSC) and detects, and its detected result is presented within the scope of 131-187 ℃ endotherm(ic)peak, within the scope of 206-248 ℃, has exothermic peak; Particularly, described 7 β, the differential scanning calorimetric analysis (DSC) of 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A detects and has located endotherm(ic)peak at 171 ± 2 ℃, at 227 ± 2 ℃, has located exothermic peak; More specifically, described 7 β, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A has differential scanning calorimetric thermogram spectrum as shown in Figure 2.
7 β, the thermogravimetric analysis (TGA) of 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A detects and occurs weight loss at 116-204 ℃, this weight loss should be that sample loses due to crystallization deuterated acetone in this temperature range, its weight loss is massfraction 5.5%-7.5%, preferred 6.0%-7.0%, more preferably 6.5%-6.9%, most preferably 6.7%.
7 β, thermogravimetric analysis (TGA) detection display of 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A, sample is being warming up to from 205 ℃ the 45%-50% that 280 ℃ of processes have been lost initial sample quality, during being warming up to 240 ℃ of processes from 215 ℃, lost the 25%-35% of initial sample quality, preferably 26%-31%; Be warming up to the process of 230 ℃ from 220 ℃, lost the 17%-27% of initial sample quality, preferably 18%-23%; The weight loss of this temperature range should be due to sample decomposes within the scope of said temperature.
Particularly, 7 β, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A has the differential scanning calorimetric analysis shown in Fig. 2 (DSC) and thermogravimetric analysis collection of illustrative plates (TGA) as shown in Figure 3.
Second aspect present invention provides a kind of 7 β, the preparation method of 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A, the method comprises the following steps: by 7 β, 10 β-dimethoxy docetaxel is dissolved in the mixed solvent of deuterated acetone and water, after standing solvent flashing, separate out, filtration, washing, dry 7 β, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A of obtaining; Wherein, this preparation method completes under 15-40 ℃ of condition, preferably 20-35 ℃, more preferably 25-30 ℃; In described deuterated acetone and the mixing solutions of water, the volume ratio of water and deuterated acetone is 1:0.1-10, preferably 1:0.5-5, more preferably 1:1-5, most preferably 1:5.
More specifically, 7 β described in a second aspect of the present invention, the preparation method of 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A comprises the following steps: by 7 β, 10 β-dimethoxy docetaxel is dissolved in the mixing solutions of deuterated acetone and water, standing volatilization 10-20 hour, suction filtration, with the mixing solutions washing leaching cake of deuterated acetone and water, 40 ℃ of vacuum-dryings obtain 7 β, the crystal form A of 10 β-dimethoxy docetaxel deuterated acetone compound; Wherein, this preparation method completes under 15-40 ℃ of condition, preferably 20-35 ℃, more preferably 25-30 ℃; In described deuterated acetone and the mixing solutions of water, the volume ratio of water and deuterated acetone is 1:0.1-10, preferably 1:0.5-5, more preferably 1:1-5, most preferably 1:5.
In preparation process of the present invention, 7 β, the mass volume ratio of the mixed solvent that 10 β-dimethoxy docetaxel and deuterated acetone and water form does not limit, as long as mixed solvent can be by 7 β, 10 β-dimethoxy docetaxel dissolves.
The present invention adopts water and deuterated acetone as the solvent crystallization of volatilizing, and pollutes littlely, and can obtain highly purified crystal formation, and HPLC purity reaches more than 99%, and technique favorable reproducibility.
The present invention also finds and 7 β, 10 β-dimethoxy docetaxel is compared, 7 β, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A has good solubility (5g/100ml ethanol) and dissolution rate at ethanol, in preparation process, can improve 7 β, the property prepared of 10 β-dimethoxy docetaxel injection, is more conducive to suitability for industrialized production.
In addition, because deuterated acetone is volatile, with 7 β, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A is the residual lower than detection limit of deuterated acetone in the injection for preparing of bulk drug, the residual of deuterated acetone do not detected, therefore there is low residue, the security that can improve medicine.
7 β provided by the present invention, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A has the purposes for the preparation of the medicine for the treatment of prostate cancer.
In sum, the invention provides a kind of 7 β, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A and preparation method thereof, this crystal formation stable in properties, purity is high, in ethanol, solvability is good, dissolution rate is fast, be conducive to improve 7 β, the property prepared of 10 β-dimethoxy docetaxel injection, is more conducive to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is 7 β, the X-ray powder diffraction of 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A;
Fig. 2 is 7 β, the thermogravimetric analysis collection of illustrative plates of 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A;
Fig. 3 is 7 β, the differential scanning calorimetric thermogram spectrum of 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A.
Embodiment
Below by specific embodiment, further illustrate the present invention, but should be understood to, these embodiment are only used for specifically describing more in detail the present invention's use, and should not be construed as, limit in any form the present invention.The material that the present invention used is in test well known in the art or can prepares according to prior art; The test method of using is well known in the art or conventional; It needs to be noted, the present invention prepares 7 β, 7 β that 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A is used, and 10 β-dimethoxy docetaxel is to prepare according to the disclosed method of embodiment 1 of WO96030355.
The inspection apparatus that the present invention is used:
(1) nuclear magnetic resonance spectrum
Instrument model: Varian INOVA-400 nuclear magnetic resonance analyser.
Test condition: solvent deuterochloroform.
(2) X-ray powder diffraction instrument
Source of radiation: Cu target Ka radiation.
Sample preparation: after sample porphyrize, be placed in standard model frame and measure.
(3) TGA/DSC1 simultaneous thermal analysis instrument
Instrument model: METTLER TGA/DSC1.
Test condition: initial measurement temperature: 30 ℃
Temperature rise rate: 10 ℃/min
Under 15 ℃ of temperature environments, by 100mg 7 β, 10 β-dimethoxy docetaxel drops into 50ml reaction flask, adds the water of 1ml and the deuterated acetone of 5ml, stirs molten clear, uncovered standing crystallization 10h, suction filtration, the mixed solvent of water and deuterated acetone (volume ratio is 45:55) washing leaching cake, 40 ℃ of vacuum-drying 2 hours, obtain 45mg needle-like crystal, HPLC purity 99%.
1H-NMR(600MHz,CDCl
3,δppm):1.20(d,3H),1.25(d,3H),1.36(s,9H),1.71(s,3H),1.79(mt,1H),1.87(s,3H),2.25-2.32(mt,2H),2.36(s,3H),2.69(mt,1H),3.30(s,3H),3.41(mt,1H),3.45(s,3H),3.82(d,1H),3.85(dd,1H),4.17(d,1H),4.30(d,1H),4.63(s,1H),4.79(s,1H),4.97(d,1H),5.27(d,1H),5.41(d,1H),5.63(d,1H),6.20(t,1H),7.31-7.41(mt,5H),7.48(t,2H),7.60(t,1H),8.09(d,2H)。
By X-ray powder diffraction (XRPD), analyze 7 β, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A, measurement result shows, this crystal formation is used Cu-Ka radiation, and the X-ray powder diffraction representing with 2 θ angles is at 8.9 ± 0.2 °, 10.3 ± 0.2 °, 12.9 ± 0.2 °, 17.7 ± 0.2 °, 19.9 ± 0.2 °, located characteristic peak for 21.9 ± 0.2 °; Also at 7.6 ± 0.2 °, 8.0 ° ± 0.2 °, 12.7 ± 0.2 °, 13.6 ± 0.2 °, 14.5 ± 0.2 °, 15.1 ± 0.2 °, 15.9 ± 0.2 °, 16.7 ± 0.2 °, 17.1 ± 0.2 °, 18.3 ± 0.2 °, 20.5 ± 0.2 °, 21.2 ± 0.2 °, 22.3 ± 0.2 °, 23.1 ± 0.2 °, located characteristic peak for 24.0 ± 0.2 °.Its representative XRPD figure is shown in accompanying drawing 1.
By embodiment 1 gained 7 β, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A detects through METTLER TGA/DSC1 simultaneous thermal analysis instrument, synchronously obtains thermogravimetric analysis collection of illustrative plates (TGA) and the means of differential scanning calorimetry collection of illustrative plates (DSC) of this sample.Measurement result shows:
1, the differential scanning calorimetric analysis of described deuterated acetone compound crystal form A detects has endotherm(ic)peak at 131-187 ℃, at 206-248 ℃, has exothermic peak;
2, the differential scanning calorimetric analysis of described deuterated acetone compound crystal form A detects and has located endotherm(ic)peak at 171 ± 2 ℃, at 227 ± 2 ℃, has located exothermic peak;
3, the thermogravimetric analysis of described deuterated acetone compound crystal form A detects and at 116-204 ℃, to locate to occur weightless, and weight loss is 5.5%~7.5% of initial sample quality, and preferably 6.0%~7.0%, more preferably 6.5%~6.9%, most preferably 6.7%;
4, the thermogravimetric analysis of described deuterated acetone compound crystal form A detects at 205-280 ℃ and continues weightlessness;
7 β, thermogravimetric analysis collection of illustrative plates (TGA) and the means of differential scanning calorimetry collection of illustrative plates (DSC) of 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A are specifically shown in accompanying drawing 2 and accompanying drawing 3.
Under 40 ℃ of temperature environments, by 50mg 7 β, 10 β-dimethoxy docetaxel drops into 25ml reaction flask, adds 0.5ml water and 2.5ml deuterated acetone, stirs molten clear, uncovered standing crystallization 20h, suction filtration, the mixed solvent of water and deuterated acetone (volume ratio is 45:55) washing leaching cake, 40 ℃ of vacuum-drying 4 hours, obtain 25mg needle-like crystal, HPLC purity 99.2%.
According to XRPD and thermogravimetric analysis and differential scanning amount data, the crystal formation obtaining is 7 β of the present invention, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A.
Embodiment 3
Under 20 ℃ of temperature environments, by 50mg 7 β, 10 β-dimethoxy docetaxel drops into 25ml reaction flask, adds 1.0ml water and 2.5ml deuterated acetone, stirs molten clear, uncovered standing crystallization 15h, suction filtration, the mixed solvent of water and deuterated acetone (volume ratio is 10:25) washing leaching cake, 40 ℃ of vacuum-drying 1 hour, obtain 24mg needle-like crystal, HPLC purity 99.5%.
According to XRPD and thermogravimetric analysis and differential scanning amount data, the crystal formation obtaining is 7 β of the present invention, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A.
Under 35 ℃ of temperature environments, by 100mg 7 β, 10 β-dimethoxy docetaxel drops into 50ml reaction flask, adds the water of 5ml and the deuterated acetone of 5ml, stir molten clear, uncovered standing crystallization 12h,, suction filtration, the mixed solvent of water and deuterated acetone (volume ratio is 45:55) washing leaching cake, 40 ℃ of vacuum-drying 3 hours, obtains 49mg needle-like crystal, HPLC purity 99.4%.
According to XRPD and thermogravimetric analysis and differential scanning amount data, the crystal formation obtaining is 7 β of the present invention, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A.
Embodiment 5
Under 25 ℃ of temperature environments, by 100mg 7 β, 10 β-dimethoxy docetaxel drops into 50ml reaction flask, adds the water of 0.5ml and the deuterated acetone of 5ml, stirs molten clear, uncovered standing crystallization 18h, suction filtration, the mixed solvent of water and deuterated acetone (volume ratio is 40:50) washing leaching cake, 40 ℃ of vacuum-drying 2 hours, obtain 47mg needle-like crystal, HPLC purity 99.6%.
According to XRPD and thermogravimetric analysis and differential scanning amount data, the crystal formation obtaining is 7 β of the present invention, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A.
Under 30 ℃ of temperature environments, by 100mg 7 β, 10 β-dimethoxy docetaxel drops into 50ml reaction flask, adds the water of 2.5ml and the deuterated acetone of 5ml, stirs molten clear, uncovered standing crystallization 15h, suction filtration, the mixed solvent of water and deuterated acetone (volume ratio is 45:55) washing leaching cake, 40 ℃ of vacuum-drying 4 hours, obtain 51mg needle-like crystal, HPLC purity 99.8%.
According to XRPD and thermogravimetric analysis and differential scanning amount data, the crystal formation obtaining is 7 β of the present invention, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A.
Embodiment 7
Under 15 ℃ of temperature environments, by 100mg 7 β, 10 β-dimethoxy docetaxel drops into 50ml reaction flask, adds the water of 25ml and the deuterated acetone of 5ml, stirs molten clear, uncovered standing crystallization 20h, suction filtration, the mixed solvent of water and deuterated acetone (volume ratio is 25:25) washing leaching cake, 40 ℃ of vacuum-drying 4 hours, obtain 50mg needle-like crystal, HPLC purity 99.5%.
According to XRPD and thermogravimetric analysis and differential scanning amount data, the crystal formation obtaining is 7 β of the present invention, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A.
Under 15 ℃ of temperature environments, by 100mg 7 β, 10 β-dimethoxy docetaxel drops into 50ml reaction flask, adds the water of 50ml and the deuterated acetone of 5ml, stirs molten clear, uncovered standing crystallization 20h, suction filtration, the mixed solvent of water and deuterated acetone (volume ratio is 55:45) washing leaching cake, 40 ℃ of vacuum-drying 4 hours, obtain 47mg needle-like crystal, HPLC purity 99.6%.
According to XRPD and thermogravimetric analysis and differential scanning amount data, the crystal formation obtaining is 7 β of the present invention, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A.Embodiment 97 β, the stability study of 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A
7 β that the present invention makes embodiment 1-8, the stability of 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A is studied, vacuum-drying at 40 ℃ (under 40mmHg pressure) 20 hours, crystal formation does not all change, 7 β that the present invention makes are described, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A is compared with 7 β, 10 β-dimethoxy docetaxel, there is satisfactory stability, be easy to preserve.
Claims (10)
1. a β, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A, it is characterized in that described crystal form A is used Cu-Ka radiation, the X-ray powder diffraction representing with 2 θ angles is at 8.9 ± 0.2 °, 10.3 ± 0.2 °, 12.9 ± 0.2 °, 17.7 ± 0.2 °, 19.9 ± 0.2 °, located characteristic peak for 21.9 ± 0.2 °; Wherein, described 7 β, in 10 β-dimethoxy docetaxel deuterated acetone compound, the content of deuterated acetone is massfraction 5.5-7.5%.
2. 7 β according to claim 1,10 β-dimethoxy docetaxel deuterated acetone compound crystal form A, is characterized in that described crystal form A, use Cu-Ka radiation, the X-ray powder diffraction representing with 2 θ angles is also at 7.6 ± 0.2 °, and 8.0 ° ± 0.2 °, 12.7 ± 0.2 °, 13.6 ± 0.2 °, 14.5 ± 0.2 °, 15.1 ± 0.2 °, 15.9 ± 0.2 °, 16.7 ± 0.2 °, 17.1 ± 0.2 °, 18.3 ± 0.2 °, 20.5 ± 0.2 °, 21.2 ± 0.2 °, 22.3 ± 0.2 °, 23.1 ± 0.2 °, located characteristic peak for 24.0 ± 0.2 °.
3. according to 7 β described in claim 1-2 any one, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A, it is characterized in that, the differential scanning calorimetric analysis of described deuterated acetone compound crystal form A detects has endotherm(ic)peak at 131-187 ℃, at 206-248 ℃, has exothermic peak.
4. 7 β according to claim 3,10 β-dimethoxy docetaxel deuterated acetone compound crystal form A, it is characterized in that, the differential scanning calorimetric analysis of described deuterated acetone compound crystal form A detects and has located endotherm(ic)peak at 171 ± 2 ℃, at 227 ± 2 ℃, has located exothermic peak.
5. according to 7 β described in claim 1-2 any one, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A, it is characterized in that, the thermogravimetric analysis of described deuterated acetone compound crystal form A detects at 116-204 ℃ and locates to occur weightlessness, and weight loss is the 5.5%-7.5% of initial sample quality.
6. 7 β according to claim 5,10 β-dimethoxy docetaxel deuterated acetone compound crystal form A, is characterized in that, the thermogravimetric analysis of described deuterated acetone compound crystal form A detect at 205-280 ℃, continue weightless.
7. prepare 7 β claimed in claim 1 for one kind, the method of 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A, it is characterized in that, the method comprises the following steps: by 7 β, 10 β-dimethoxy docetaxel is dissolved in the mixed solvent of deuterated acetone and water, standing solvent flashing, suction filtration, washing, dry, obtain 7 β, 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A.
8. preparation 7 β according to claim 7, the method of 10 β-dimethoxy docetaxel deuterated acetone compound crystal form A, it is characterized in that, the method comprises the steps: 7 β, and 10 β-dimethoxy docetaxel is dissolved in the mixing solutions of deuterated acetone and water, standing volatilization 10-20 hour, the solid that suction filtration is separated out, washing, 40 ℃ of vacuum-dryings obtain 7 β, the crystal form A of 10 β-dimethoxy docetaxel deuterated acetone compound.
9. according to the preparation method described in claim 7-8 any one, it is characterized in that, described preparation method completes under 15-40 ℃ of temperature environment.
10. according to the preparation method described in claim 7-8 any one, it is characterized in that, in described deuterated acetone and the mixing solutions of water, the volume ratio of water and deuterated acetone is 1:0.1-10, preferably 1:1-5.
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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 |
CN102675257A (en) * | 2012-05-10 | 2012-09-19 | 上海金和生物技术有限公司 | Cabazitaxel crystal and preparation method thereof |
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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 |
WO2005115454A2 (en) * | 2004-05-07 | 2005-12-08 | Massachusetts Institute Of Technology | Methods and compositions for cancer treatment relating to brca1 brct domain recognition of phosphorylated bach1 |
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 |
CN102675257A (en) * | 2012-05-10 | 2012-09-19 | 上海金和生物技术有限公司 | Cabazitaxel crystal and preparation method thereof |
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