WO2015000165A1 - Stable transformation product of dimethoxy docetaxel mono-acetonate and crystalline forms thereof, and methods for preparation of same - Google Patents

Stable transformation product of dimethoxy docetaxel mono-acetonate and crystalline forms thereof, and methods for preparation of same Download PDF

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WO2015000165A1
WO2015000165A1 PCT/CN2013/078847 CN2013078847W WO2015000165A1 WO 2015000165 A1 WO2015000165 A1 WO 2015000165A1 CN 2013078847 W CN2013078847 W CN 2013078847W WO 2015000165 A1 WO2015000165 A1 WO 2015000165A1
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preparation
acetonate
dimethoxy docetaxel
docetaxel
hours
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PCT/CN2013/078847
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French (fr)
Chinese (zh)
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王海勇
孙天宇
来庚
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北京新天宇科技开发有限公司
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Priority to PCT/CN2013/078847 priority Critical patent/WO2015000165A1/en
Publication of WO2015000165A1 publication Critical patent/WO2015000165A1/en

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    • 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 present invention relates to the field of medicinal chemistry, and in particular to a stable transformant of dimethoxy docetaxel monoacetonate, dimethoxy docetaxel-acetonate
  • Solid drugs are classified as crystalline and amorphous (amorphous).
  • the basic unit constituting the crystal of the drug is a crystal lattice in which the drug molecules are arranged in a certain regular pattern; and the amorphous form is that the molecules are arranged in an disorderly manner without a clear crystal lattice.
  • a crystalline solvent molecule is included in the drug crystal, it is called a solvate, and when the solvent is water (i.e., contains crystal water), it is generally called a hydrate.
  • the solid drug may have a different crystal form, or there may be a crystalline form and an amorphous form, or the presence of an unsolvate and a solvate, or no or water of crystallization, it is referred to as a polymorphism in the drug.
  • the different crystal forms of the drug are caused by the difference in the arrangement of the molecules in the crystal lattice.
  • the drugs with polymorphism may have different chemical and physical properties, such as different melting points, due to different lattice energies. , chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure and density, etc.
  • Polymorphic drugs may have an influence on the preparation of the drug substance and the preparation, the stability of the drug substance and the preparation, the dissolution rate of the preparation, and the bioavailability due to the difference in physical and chemical properties between the different crystal forms.
  • different apparent solubility results in different dissolution rates of the formulation and may result in different bioavailability
  • different optical and mechanical properties, density, etc. may affect the preparation process of the formulation
  • different chemical reactivity may lead to drug stability difference. Differences in drug dissolution, bioavailability, stability, etc., may affect the quality controllability, safety, and effectiveness of the drug.
  • Powder X-ray diffraction is a commonly used method for studying and distinguishing different crystal forms. This method can be used not only for the qualitative differentiation of different crystal forms, but And after establishing the quantitative relationship between the characteristic diffraction peak and the different crystal form content, powder X-ray diffraction (XPRD) can also be used for quantitative control of different crystal form ratios.
  • XPRD powder X-ray diffraction
  • Dimethoxy docetaxel chemical name: 4-acetoxy-2 ⁇ -benzoyloxy-5 ⁇ , 20-epoxy-1-hydroxy-7 ⁇ , 10 ⁇ -dimethoxy-9-oxo Taxane-11-ene-13 ⁇ -based
  • 3-phenylproplonate also commonly referred to as 7B, 1 OB-dimethoxy docetaxel, or cabazitaxel (hereinafter referred to as "Kappa", CAS No.: 183133-96- 2)
  • Kappa CAS No.: 183133-96- 2
  • Cabazitaxel can be prepared by the international application WO 9630355 or the international application WO 9925704, however the product obtained according to the method of these applications is not a crystalline substance.
  • a drug has a plurality of crystal forms
  • some crystal forms may not be easily formed or obtained, and only a part of the crystal form can be formed during the production and preparation of the drug substance and its preparation. Therefore, the focus of research and development should be on the crystal forms that may be formed during the preparation of the drug substance, the preparation of the drug, and the storage of the drug and the preparation.
  • the effects of polymorphism on the stability of the drug substance and formulation, on the dissolution and bioavailability of the formulation, and on the preparation process of the drug substance and preparation should be considered in the development process.
  • the preparation of the above crystal forms 8, C, D, E and F has a number of disadvantages, including preparation procedures It is cumbersome, for example, the preparation of crystalless C, D, E; or the preparation conditions are harsh, for example, the crystalless type B and E need to be treated at a temperature of 100 ° C or higher for a long time. It is known that the melting point or decomposition point of these two crystal forms of cabazitaxel is about 150 ° C. Long-term high temperature treatment tends to cause decomposition of the product, eventually leading to an increase in impurities and a decrease in purity.
  • the preparation of heteronuclear crystals of the same crystal form, including cabazitaxel ethanolate or ethanol/water isocyanate is more complicated, and must be prepared without crystal form, and then can be prepared on the basis of the latter.
  • the stability of crystalline materials is significantly better than the corresponding amorphous materials.
  • Kappastat has a high molecular weight, a complex structure, and a large number of polar groups in the molecule. Therefore, the drug substance in the form of crystal has the advantages of long effective period and better quality.
  • the active ingredient of capsaicin in Shangyu in June 2010 is crystal form A prepared by using cabazitaxel-acetonate.
  • the generic name is Cabazitaxel. Trade name: JEVTANA), that is, a preparation prepared from the crystal form A.
  • one of the objects of the present invention is to provide a stable transformant of dimethoxy docetaxel-acetonate.
  • Another object of the present invention is to provide a crystalline form of a dimethoxy docetaxel-acetonate stable transformant.
  • a further object of the present invention is to provide a stable transformant of dimethoxy docetaxel monoacetonate and a process for preparing the crystalline form thereof.
  • the stable transformant of dimethoxy docetaxel monoacetonate has the following structural formula:
  • the crystalline form of the dimethoxy docetaxel-acetonate stable transformant provided by the present invention is a crystalline form of dipentate docetaxel penta-one acetonide, designated as Form G, which is contained in X- Ray powder diffraction (XRPD) analysis of the spectrum by 2 ⁇
  • XRPD X- Ray powder diffraction
  • the diffraction angles of 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 11.1, 13.5 and 10.5 ⁇ 0.2° are shown. That is, the crystal form G was characterized by X-ray powder diffraction pattern to show characteristic peaks including 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 11.1, 13.5, and 15.0 ⁇ 0.2 ° 2 ⁇ .
  • the crystal form G of the diacetate docetaxel penta-one acetonide provided by the present invention is more contained in 7.2, 7.4, 7.8, 8.1 represented by 2 ⁇ in the X-ray powder diffraction analysis chart. 8.8, 9.8, 10.2, 10.4, 11.1, 13.5, 14.3, 15.0 and 15.2 ⁇ 0.2° diffraction angle. Namely, the crystal form G was characterized by X-ray powder diffraction pattern to show characteristic peaks including 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 10.2, 10.4, 11.1, 13.5, 14.3, 15.0 and 15.2 ⁇ 0.2 ° 2 ⁇ .
  • the crystal form G of the diacetate docetaxel pentaacetate provided by the present invention is more, and includes 7.2, 7.4, 7.8, 8.1 represented by 2 ⁇ in the X-ray powder diffraction analysis spectrum. Diffusion angles of 8.8, 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0 and 15.2 ⁇ 0.2°. That is, the crystal form G is characterized by X-ray powder diffraction pattern to include 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0, and 15.2 ⁇ 0.2 ° 2 ⁇ Characteristic peak.
  • the crystal form G of the diacetate docetaxel pentaacetate provided by the present invention is more, and includes 7.2, 7.4, 7.8, 8.1 represented by 2 ⁇ in the X-ray powder diffraction analysis spectrum. 8.8, 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0, 15.2, 15.7, 16.3, 16.5, 17.1, 17.6, 17.9 ⁇ 0.2° diffraction angle.
  • the crystallization of the Form G by X-ray powder diffraction pattern shows that it is located at 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0, 15.2, 15.7, 16.3, 16.5, 17.1, 17.6, 17.9 ⁇ 0.2 ° 2 ⁇ characteristic peak.
  • crystal forms of the already disclosed cabazitaxel include crystal forms VIII, B, C, D, E and F, the specific data (characteristic peaks represented by the diffraction angle of 2 )) are: crystalline form ⁇ : disclosed for international application WO200480026128, but Specific values are not listed, only their XRPD maps are listed, see Figure 1 of which it is disclosed.
  • Form ⁇ For the international application WO200980102389, the characteristic peaks are 7.3, 8.1, 9.8, 10.4, 11.1, 12.7, 13.1, 14.3, 15.4 and 15.9 ⁇ 0.2°.
  • Form C disclosed for international application WO200980102389, with characteristic peaks of 4.3, 6.8, 7.4, 8.7, 10.1, 11.1, 11.9, 12.3, 12.6 and 13.1 ⁇ 0.2°.
  • Form D disclosed for international application WO200980102389, with characteristic peaks of 3.9, 7.7, 7.8, 7.9, 8.6, 9.7, 10.6,
  • Form E As disclosed in the international application WO200980102389, the characteristic peaks are 7.1, 8.1, 8.9, 10.2, 10.8, 12.5, 12.7 (extremely weak peaks, negligible), 13.2, 13.4 and 13.9 ⁇ 0.2°.
  • Form F For the international application WO200980102389, the characteristic peaks are 4.4, 7.2, 8.2, 8.8, 9.6, 10.2, 10.9, 11.2, 12.1 and 12.3 ⁇ 0.2. .
  • crystal forms C, D, and F have a characteristic peak of 2 ⁇ of 4.3, 3.9, and 4.4, respectively, which is significantly different from the crystalline form of the present invention; although crystal form A does not list specific data in the literature, it is from the map. It can also be clearly seen that there is no 2 ⁇ characteristic peak data below 8.5°; the characterization data of crystal forms B and E are relatively similar, and in the range of 0.2°, most of the data are consistent, including 7.3 and 7.1.
  • the XRPD data of the present invention (characteristic peaks represented by the diffraction angle of 2 ⁇ ) are 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0, 15.2.
  • the most significant difference from Forms B and E is the portion of the 2 ⁇ diffraction angle below 10, including 7.2, 7.4, 7.8, 8.1, 8.8, 9.8°, especially between 7 and 8 where dense fingerprint areas appear.
  • the diffraction angles other than this are consistent with Forms B and E, including: 10.2, 10.4, 11.1, 12.6,
  • the invention provides a method for preparing a stable transformant of dimethoxy docetaxel monoacetonate, comprising: dissolving dimethoxy docetaxel (carbataxel) monoacetonate under vacuum in the presence of a desiccant or In the absence of the condition, heat at 40 ⁇ 60 °C for 24 ⁇ 120 hours.
  • the heating time is preferably 24 to 96 hours, more preferably 30 to 96 hours, and most preferably 48 to 96 hours.
  • the preparation method of the dimethoxy docetaxel divalent acetone of the present invention comprises: dimethoxy-docetaxel (carbataxel)-acetonate under vacuum, drying Heat at 40 ⁇ 60 ° C for 24 hours in the presence or absence of the agent.
  • the preparation method of the diacetate docetaxel penta acetonide comprises: dimethoxy docetaxel (carbataxel) monoacetonate Under vacuum conditions, in the presence or absence of a desiccant, heat at 40 to 60 ° for 48 to 96 hours.
  • the heating temperature is preferably 55 °C. That is, in the preparation of diacetate docetaxel acetonide and dimethoxy docetaxel penta acetonate, the temperature may preferably be 55 °C.
  • the desiccant may be selected from anhydrous calcium chloride or phosphorus pentoxide, preferably anhydrous calcium chloride.
  • the heating can be stopped at any time, and the heating time can be accumulated to the above range. It is not necessary to be a vacuum condition for the intermittent heating stop, and it is preferred to maintain the vacuum condition.
  • the present invention overcomes the shortcomings of the prior art cabazitaxel-acetonate instability, and a stable conversion of dimethoxy docetaxel (cabbataxel) monoacetonate can be found by simple treatment.
  • the product prepared by the invention can last for a long time under relatively harsh conditions, the state does not change, and the product has good stability; and the existing cabazitaxel-acetonate continues under similar conditions. The conversion occurred in a very short time, indicating that it is very unstable.
  • the preparation method of the invention is simple, and the stable product (especially one-fifth acetonide and its crystalline form) satisfying the pharmaceutical requirement can be obtained without preparing the crystal-free type; Long-term high temperature treatment minimizes the temperature-related impurities, ensuring product quality and thus contributing to patient health.
  • the one-fifth of the acetonide of the present invention has higher stability than the above-mentioned cappastamine drug substance, and the quality of the preparation made of the drug substance is better, and the cost is indirectly lowered (yew Alkane anticancer drugs are extremely expensive, and the active feedstock contains less acetone and is therefore more safe.
  • Figure 1 is an HNMR spectrum of an amorphous cabazitaxel bulk drug.
  • Figure 2 is an H NMR spectrum of the cabazitaxel monoacetonate obtained in accordance with Example 1.
  • Figure 3 shows the H NMR spectrum of cabazitaxel-acetonate treated under vacuum at 55 ° C for 24 hours with a acetone content of 3.2%, i.e. containing one-half of acetone.
  • Figure 4 shows the H NMR spectrum of cabazitaxel-acetonate treated under vacuum at 55 ° C for 48 hours.
  • the acetone content in the spectrum is 1.3%, i.e., contains one-fifth of acetone molecules.
  • Figure 5 shows the H NMR spectrum of cabazitaxel-acetonate treated under vacuum at 55 ° C for 72 hours with an acetone content of 1.3%, i.e. still containing one-fifth of acetone molecules.
  • Figure 6 shows the TGA spectrum of cabazitaxel-acetonate treated under vacuum at 55 ° C for 72 hours.
  • the acetone content in the spectrum is 1.3%, which still contains one-fifth of acetone molecules.
  • Figure 7 shows XPRD spectra of cabazitaxel-acetonate treated under vacuum at 55 °C for 72 hours.
  • Figure 8 shows the H NMR spectrum of a kappataxel-acetonate treated under vacuum at 55 ° C for 96 hours.
  • the acetone content in the spectrum was 1.3%, i.e., still contained one-fifth of acetone molecules.
  • Figure 9 is a HPLC chart of the solution obtained in accordance with Example 4 after standing at 25 ° C for 6 months. detailed description
  • tube pressure 45 kV
  • 26 6 scanning range 5 ⁇ 50 ° step length 0.015 °
  • X-ray powder diffraction experimental data Reflected at a diffraction angle of 2 ⁇ A theoretical discussion of X-ray powder diffraction patterns can be found in "X-ray diffraction procedures", ⁇ . P. Klug and L. E. Alexander, J. Wiley, New York (1974).
  • the amorphous cabazitaxel material of the present invention is prepared by the method described in Chinese patent application CN 96192884, and the quality of the raw material is determined by HPLC: the content is >99%, and the single impurity is less than 0.15%. It was analyzed and analyzed to obtain an HNMR spectrum as shown in Fig. 1, and it was clearly observed that the moisture and the organic solvent were not contained in the spectrum.
  • Example 1 of International Application WO2004800261208 2 mL of purified water was added to a solution of 500 mg of cabazitaxel in 4.8 mL of acetone, followed by seeding of a suspension of 5 mg of cabazitaxel in 0.05 mL of water and 0.05 mL of acetone. After the mixture was stirred for 16 hours, 3.6 mL of purified water was added, then stirred for 1 hour, filtered, and the filter cake was washed with a mixture of 1 mL of acetone and 1.3 mL of water.
  • the product was dried under reduced pressure in a vacuum drying oven by an oil pump, and treated at 55 ° C for 24 hours to obtain a target product (ie, one-part acetone of cabazitaxel).
  • NMR showed an acetone content of 3.2% (see Figure 3).
  • the product was dried under reduced pressure in an air drying oven, and the treatment was continued at 55 ° C for 24 hours (ie, 48 hours in total) to obtain the target product (ie, One-fifth of the acetonide in cabazitaxel, in crystalline form, NMR showed an acetone content of 1.3% (see Figure 4).
  • one-fifth of the effervescent of cabazitaxel was continuously dried in a vacuum drying oven with an oil pump, and the product was treated at 55 ° C for 24 h (i.e., total 72 h) without change, and the target product was still obtained.
  • NMR showed an acetone content of 1.3% (see Figure 5);
  • TGA showed an acetone content of 1.3% (see Figure 6);
  • the structure of the one-fibrate acetonide of cabazitaxel according to the present invention can be determined by nuclear magnetic resonance and TGA, and the acetone contained in the molecule can be obtained by nuclear magnetic resonance method and TGA. Good qualitative and quantitative, and the two methods have a good correlation.
  • the crystal form G of one-fifth of the effervescent of cabazitaxel is continuously dried in a vacuum drying oven by an oil pump, and the product is still unchanged after being treated at 55 ° C for 24 hours (ie, 96 hours in total), that is, The target product was still obtained, and NMR showed an acetone content of 1.3% (see Figure 8).
  • the XPRD spectrum of the one-fibrous acetonate form G of cabazitaxel obtained by the third method is substantially the same as that of Fig. 7.
  • the cabazitaxel monoacetonate obtained by the method of Example 1 was continuously placed in a vacuum drying oven, and vacuum was obtained by decompression with an oil pump in the presence of anhydrous calcium chloride, and then dried at 40 ° C for 120 hours to obtain a kappa.
  • the cabazitaxel-acetonate obtained as in the method of Example 1 was continuously placed in a vacuum drying oven, and a vacuum was obtained by decompression with an oil pump in the presence of anhydrous calcium chloride, followed by drying at 60 ° C for 48 hours to obtain a kappa.
  • Example 4 On the basis of the method disclosed in Example 1, there is no disclosure in the literature that others continue to react to obtain a stable conversion of cabazitaxel containing acetone. The inventors continued research and improvement on the basis of the prior art (lack of product stability), and eliminated a large number of interfering factors (which generate a large number of unstable transformants). After long-term and trial and error exploration, the inventors finally determined. this invention.
  • Example 4 On the basis of the method disclosed in Example 1, there is no disclosure in the literature that others continue to react to obtain a stable conversion of cabazitaxel containing acetone. The inventors continued research and improvement on the basis of the prior art (lack of product stability), and eliminated a large number of interfering factors (which generate a large number of unstable transformants). After long-term and trial and error exploration, the inventors finally determined. this invention. Example 4
  • the capsaid product of Cabazitaxel (trade name: JEVTANA) is a 60 mg/1.5 mL original solution: contains 60 mg of cabazitaxel-acetonate and 1.5 mL of polysorbate 80.
  • a two-step dilution is required before administration to the patient. The first step is: Dilute the original solution to a 10 mg/mL mixed solution using 5.7 mL of 13% (w/w) aqueous ethanol solution; the second step is: The one-step dilution solution is transferred to 250 mL of 0.9% sodium chloride solution or 5% glucose solution for injection.
  • the raw material drug product obtained in the second method of the third embodiment was prepared by using the polysorbate 80 as a solvent, and a solution having a concentration of 60 mg/1.5 mL was also smoothly prepared. After the solution was allowed to stand at 25 ° C for 6 months, HPLC showed that the product was very stable (see Figure 9), and the same two-step dilutions as JEVTANA were used to obtain the exact same product.
  • the dimethoxy docetaxel (carbataxel) acetonide provided by the invention, and the corresponding crystalline form have higher stability, and use them as a raw material medicine to prepare a pharmaceutical preparation having anticancer and anti-leukemia effects, Facilitating the quality control of the product will make the preparation product have a longer effective period and better quality; at the same time, the active raw material contains less acetone and thus has higher safety.

Abstract

Provided are a stable transformation product of dimethoxy docetaxel mono-acetonate, crystalline forms thereof, and methods for the preparation of same. The stable transformation product and the crystalline forms thereof are higher in stability, thus pharmaceutical preparations obtained by using the stable transformation product and the crystalline forms as raw materials is endowed with better quality, longer effective duration and higher safety.

Description

二甲氧基多西紫杉醇一丙酮化物的稳定转化物 及其结晶形式、 以及它们的制备方法 技术领域  Stable conversion of dimethoxy docetaxel monoacetonate and its crystalline form, and preparation method thereof
本发明涉及药物化学领域， 具体地， 涉及二甲氧基多西紫杉醇一 丙酮化物的稳定转化物，二甲氧基多西紫杉醇一丙酮化  The present invention relates to the field of medicinal chemistry, and in particular to a stable transformant of dimethoxy docetaxel monoacetonate, dimethoxy docetaxel-acetonate
的结晶形式， 以及它们的制备方法。 背景技术 Crystallized forms, and methods for their preparation. Background technique
固体药物有结晶型和非结晶型（无定形）之分。 构成药物结晶的 基本单元为晶格， 在晶格中药物分子以一定的规律排列； 而无定形是 分子以无序的方式排列， 不具有明确的晶格。 若药物结晶中包含结晶 溶剂分子， 就称为溶剂化物， 当该溶剂为水时 （即含有结晶水）， 通 常称为水合物。 如果固体药物可存在不同的晶型， 或存在结晶型与无 定形， 或存在非溶剂化物与溶剂化物、 不含或含有结晶水等现象， 就 称为该药物存在多晶型现象。  Solid drugs are classified as crystalline and amorphous (amorphous). The basic unit constituting the crystal of the drug is a crystal lattice in which the drug molecules are arranged in a certain regular pattern; and the amorphous form is that the molecules are arranged in an disorderly manner without a clear crystal lattice. If a crystalline solvent molecule is included in the drug crystal, it is called a solvate, and when the solvent is water (i.e., contains crystal water), it is generally called a hydrate. If the solid drug may have a different crystal form, or there may be a crystalline form and an amorphous form, or the presence of an unsolvate and a solvate, or no or water of crystallization, it is referred to as a polymorphism in the drug.
药物的不同晶型是由分子在晶格中排列方式的不同所致，存在多 晶型现象的药物由于晶格能的不同，其不同晶型可具有不同的化学和 物理性质， 如不同的熔点、 化学反应性、 表观溶解度、 溶出速率、 光 学和机械性质、 蒸汽压和密度等。 多晶型药物由于不同晶型之间理化 性质的不同， 可能对原料药及制剂的制备， 原料药及制剂的稳定性， 制剂的溶出度及生物利用度等产生影响。比如不同的表观溶解度致使 制剂有不同的溶出度， 并可能导致生物利用度的不同； 不同的光学和 机械性质、 密度等可能影响制剂的制备工艺； 不同的化学反应性可导 致药品稳定性的差异。 药品溶出度、 生物利用度、 稳定性等的差异进 而可能影响药品的质量可控性、 安全性和有效性。  The different crystal forms of the drug are caused by the difference in the arrangement of the molecules in the crystal lattice. The drugs with polymorphism may have different chemical and physical properties, such as different melting points, due to different lattice energies. , chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure and density, etc. Polymorphic drugs may have an influence on the preparation of the drug substance and the preparation, the stability of the drug substance and the preparation, the dissolution rate of the preparation, and the bioavailability due to the difference in physical and chemical properties between the different crystal forms. For example, different apparent solubility results in different dissolution rates of the formulation and may result in different bioavailability; different optical and mechanical properties, density, etc. may affect the preparation process of the formulation; different chemical reactivity may lead to drug stability difference. Differences in drug dissolution, bioavailability, stability, etc., may affect the quality controllability, safety, and effectiveness of the drug.
由于多晶型问题可能影响药品的安全有效性和质量可控性，应当 针对不同情况釆取相应的措施。 粉末 X -射线衍射是常用的研究和区 分不同晶型的有效方法， 该方法不仅可用于不同晶型的定性区分， 而 且在建立特征衍射峰与不同晶型含量之间的定量关系后， 粉末 X - 线衍射（XPRD )还可用于不同晶型比例的定量控制。 Since the polymorphic problem may affect the safety and efficacy of the drug and the quality controllability, corresponding measures should be taken for different situations. Powder X-ray diffraction is a commonly used method for studying and distinguishing different crystal forms. This method can be used not only for the qualitative differentiation of different crystal forms, but And after establishing the quantitative relationship between the characteristic diffraction peak and the different crystal form content, powder X-ray diffraction (XPRD) can also be used for quantitative control of different crystal form ratios.
二甲氧基多西紫杉醇， 化学名为： 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-氧代紫杉 -11-烯 -13α-基  Dimethoxy docetaxel, chemical name: 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1-hydroxy-7β, 10β-dimethoxy-9-oxo Taxane-11-ene-13α-based
( 2R,3S ) -3-叔丁氧基羰基氨基 -2-羟基 -3-苯基丙酸酯 （4-acetoxy- ( 2R,3S ) -3-tert-Butoxycarbonylamino-2-hydroxy-3-phenylpropionate (4-acetoxy-
2a-benzoyloxy-5 , 20-epoxy- 1 -hydroxy-7 , 1 Οβ-dlmethoxy- 9-oxotax- l l-en-13a-yl ( 2R,3S ) -3-tert-butoxycarbonylamino-2-hydroxy-2a-benzoyloxy-5 , 20-epoxy- 1 -hydroxy-7 , 1 Οβ-dlmethoxy- 9-oxotax- l l-en-13a-yl ( 2R,3S ) -3-tert-butoxycarbonylamino-2-hydroxy-
3-phenylproplonate ), 通常也可以称为 7B, 1 OB-二甲氧基多西紫杉醇 ( dimethoxy docetaxel ), 或者卡巴他赛（本发明以下统称为 "卡巴他 赛"， CAS号： 183133-96-2 ), 具有显著的抗癌和抗白血病功效， 研究 表明其即为存在上述多晶型现象的物质。 3-phenylproplonate), also commonly referred to as 7B, 1 OB-dimethoxy docetaxel, or cabazitaxel (hereinafter referred to as "Kappa", CAS No.: 183133-96- 2), has significant anti-cancer and anti-leukemia effects, studies have shown that it is the presence of the above polymorphism.
卡巴他赛以及相关结晶形式的制备可以根据以下申请中的具体 描述方法完成：  The preparation of cabazitaxel and related crystalline forms can be accomplished according to the specific description in the following application:
国际申请 WO 9630355或国际申请 WO 9925704可以制备得到卡 巴他赛， 然而根据这些申请中的方法获得的产物并不是晶体物质。  Cabazitaxel can be prepared by the international application WO 9630355 or the international application WO 9925704, however the product obtained according to the method of these applications is not a crystalline substance.
国际申请 WO 200480026128公开了第一种卡巴他赛晶体化合物 一一卡巴他赛一丙酮溶剂化物， 并进行了表征， 确定为晶型 A。  International application WO 200480026128 discloses a first type of cabazitaxel crystalline compound, a cabazitaxel-acetone solvate, and is characterized as crystal form A.
国际申请 WO 200980102389公开了卡巴他赛的乙醇化物、水合物 及无水合物的五种晶型， 分别是经由晶型 A制备出晶型 B、 C、 D、 E 和 F, 以及它们的制备方法， 并对其中部分晶型进行了表征。  International application WO 200980102389 discloses five crystal forms of ethanol, hydrate and anhydrate of cabazitaxel, which are prepared by crystal form A, respectively, crystal forms B, C, D, E and F, and preparation methods thereof And some of the crystal forms were characterized.
然而， 一种药物虽然存在多种晶型， 但某些晶型可能不易形成或 得到， 仅有部分晶型在原料药及其制剂的生产制备过程中能够形成。 因此， 研发工作中重点应考虑那些在原料药制备、 制剂制备、 以及原 料药及制剂贮藏过程中可能形成的晶型。 对于存在多晶型现象的药 物， 研发过程中需要考虑多晶型对原料药及制剂稳定性、 对制剂溶出 及生物利用度的影响， 以及对原料药及制剂制备工艺的影响。  However, although a drug has a plurality of crystal forms, some crystal forms may not be easily formed or obtained, and only a part of the crystal form can be formed during the production and preparation of the drug substance and its preparation. Therefore, the focus of research and development should be on the crystal forms that may be formed during the preparation of the drug substance, the preparation of the drug, and the storage of the drug and the preparation. For the presence of polymorphism, the effects of polymorphism on the stability of the drug substance and formulation, on the dissolution and bioavailability of the formulation, and on the preparation process of the drug substance and preparation should be considered in the development process.
上述晶型8、 C、 D、 E和 F的制备存在诸多缺点， 包括制备程序 繁瑣， 例如无水晶型 C、 D、 E的制备； 或者制备条件苛刻， 例如无水 晶型 B和 E需要在 100°C或更高温度下进行长时间处理。 已知这几种晶 型的卡巴他赛的熔点或者分解点在 150°C左右， 长时间高温处理易引 起产品分解，最终导致杂质增多，纯度降低。而相同晶型的异核晶体, 包括卡巴他赛乙醇化物或者乙醇 /水异溶剂化物的制备更是复杂， 必 须先制备出无水晶型， 然后在后者的基础上才能制备出来。 The preparation of the above crystal forms 8, C, D, E and F has a number of disadvantages, including preparation procedures It is cumbersome, for example, the preparation of crystalless C, D, E; or the preparation conditions are harsh, for example, the crystalless type B and E need to be treated at a temperature of 100 ° C or higher for a long time. It is known that the melting point or decomposition point of these two crystal forms of cabazitaxel is about 150 ° C. Long-term high temperature treatment tends to cause decomposition of the product, eventually leading to an increase in impurities and a decrease in purity. The preparation of heteronuclear crystals of the same crystal form, including cabazitaxel ethanolate or ethanol/water isocyanate, is more complicated, and must be prepared without crystal form, and then can be prepared on the basis of the latter.
一般情况下， 晶体物质的稳定性显著优于相应的无定型物质。 卡 巴他赛分子量较高， 结构复杂， 分子中具有较多的极性基团， 因而， 其以晶体形式存在的原料药具有有效期长、质量更佳的优点。 虽然已 经公开的卡巴他赛晶型较多， 然而， 于 2010年 6月上巿的卡巴他赛活 性成分为卡巴他赛一丙酮化物制备得到的晶型 A, 通用名为卡巴他赛 ( Cabazitaxel, 商品名： JEVTANA ), 即由该晶型 A制备的制剂。  In general, the stability of crystalline materials is significantly better than the corresponding amorphous materials. Kappastat has a high molecular weight, a complex structure, and a large number of polar groups in the molecule. Therefore, the drug substance in the form of crystal has the advantages of long effective period and better quality. Although there are many crystal forms of cabazitaxel that have been disclosed, the active ingredient of capsaicin in Shangyu in June 2010 is crystal form A prepared by using cabazitaxel-acetonate. The generic name is Cabazitaxel. Trade name: JEVTANA), that is, a preparation prepared from the crystal form A.
然而， 研究表明： A晶型的卡巴他赛一丙酮化物稳定性较差， 分 子中的丙酮易分解，严重影响原料药的质量控制， 进而必定影响到其 制剂的有效性和安全性。 因而， 有必要找到更加合适的卡巴他赛， 即 二甲氧基多西紫杉醇一丙酮化物的稳定转化物，以及二甲氧基多西紫 杉醇一丙酮化物稳定转化物新的结晶形式。 发明内容  However, studies have shown that: A crystal form of cabazitaxel-acetonate is less stable, and acetone in the molecule is easily decomposed, which seriously affects the quality control of the drug substance, which in turn affects the effectiveness and safety of the preparation. Thus, it is necessary to find a more suitable kappastat, a stable conversion of dimethoxy docetaxel monoacetonate, and a new crystalline form of dimethoxy docetaxel-acetonate stable transformant. Summary of the invention
为了解决现有技术中存在的问题， 本发明的目的之一在于， 提供 二甲氧基多西紫杉醇一丙酮化物的稳定转化物。  In order to solve the problems in the prior art, one of the objects of the present invention is to provide a stable transformant of dimethoxy docetaxel-acetonate.
本发明的另一目的在于，提供二甲氧基多西紫杉醇一丙酮化物稳 定转化物的结晶形式。  Another object of the present invention is to provide a crystalline form of a dimethoxy docetaxel-acetonate stable transformant.
本发明的又一目的在于，提供二甲氧基多西紫杉醇一丙酮化物的 稳定转化物及其结晶形式的制备方法。  A further object of the present invention is to provide a stable transformant of dimethoxy docetaxel monoacetonate and a process for preparing the crystalline form thereof.
本发明提供的二甲氧基多西紫杉醇一丙酮化物的稳定转化物，结 构式如下： The stable transformant of dimethoxy docetaxel monoacetonate provided by the invention has the following structural formula:
Figure imgf000006_0001
Figure imgf000006_0001
其中， X=l/2或 1/5。  Where X = l/2 or 1/5.
也就是说：  That is:
本发明提供的二甲氧基多西紫杉醇一丙酮化物的稳定转化物，可 以为二甲氧基多西紫杉醇（卡巴他赛）二分之一丙酮化物， 结构式如 下 （当 X=l/2时）：  The stable transformant of dimethoxy docetaxel monoacetonate provided by the invention may be diacetate docetaxel (carbataxel) one-half acetone, and the structural formula is as follows (when X=l/2) ):
Figure imgf000006_0002
Figure imgf000006_0002
本发明提供的二甲氧基多西紫杉醇一丙酮化物的稳定转化物，也 可以为二甲氧基多西紫杉醇（卡巴他赛）五分之一丙酮化物， 结构式 如下 (当 X=l/5时）：  The stable transformant of dimethoxy docetaxel monoacetonate provided by the invention may also be one-fifth acetone of dimethoxy docetaxel (carbataxel), and the structural formula is as follows (when X=l/5) Time):
Figure imgf000006_0003
Figure imgf000006_0003
本发明提供的二甲氧基多西紫杉醇一丙酮化物稳定转化物的结 晶形式， 为二甲氧基多西紫杉醇五分之一丙酮化物的结晶形式，命名 为晶型 G, 其包含在 X-射线粉末衍射（XRPD )分析谱图中由 2 Θ表 示的 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 11.1、 13.5和 15.0士 0.2°的衍射 角。 即， 晶型 G通过 X-射线粉末衍射图谱表征显示了包含 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 11.1、 13.5和 15.0士 0.2° 2 Θ的特征峰。 The crystalline form of the dimethoxy docetaxel-acetonate stable transformant provided by the present invention is a crystalline form of dipentate docetaxel penta-one acetonide, designated as Form G, which is contained in X- Ray powder diffraction (XRPD) analysis of the spectrum by 2 Θ The diffraction angles of 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 11.1, 13.5 and 10.5 ± 0.2° are shown. That is, the crystal form G was characterized by X-ray powder diffraction pattern to show characteristic peaks including 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 11.1, 13.5, and 15.0 ± 0.2 ° 2 。.
本发明提供的二甲氧基多西紫杉醇五分之一丙酮化物的晶型 G, 更多地，包含在 X-射线粉末衍射分析图谱图中由 2 Θ表示的 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 13.5、 14.3、 15.0 和 15.2 士 0.2°的衍射角。 即， 晶型 G通过 X-射线粉末衍射图谱表征显示了包含 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 13.5、 14.3、 15.0 和 15.2士 0.2° 2 Θ的特征峰。  The crystal form G of the diacetate docetaxel penta-one acetonide provided by the present invention is more contained in 7.2, 7.4, 7.8, 8.1 represented by 2 Θ in the X-ray powder diffraction analysis chart. 8.8, 9.8, 10.2, 10.4, 11.1, 13.5, 14.3, 15.0 and 15.2 ± 0.2° diffraction angle. Namely, the crystal form G was characterized by X-ray powder diffraction pattern to show characteristic peaks including 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 10.2, 10.4, 11.1, 13.5, 14.3, 15.0 and 15.2 ± 0.2 ° 2 。.
本发明提供的二甲氧基多西紫杉醇五分之一丙酮化物的晶型 G, 更多地， 包含在 X-射线粉末衍射分析谱图中由 2 Θ表示的 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 12.6、 12.9、 13.5、 14.3、 15.0 和 15.2士 0.2° 的衍射角。 即， 晶型 G通过 X-射线粉末衍射图谱表征 显示了包含 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 12.6、 12.9、 13.5、 14.3、 15.0和 15.2士 0.2° 2 Θ的特征峰。  The crystal form G of the diacetate docetaxel pentaacetate provided by the present invention is more, and includes 7.2, 7.4, 7.8, 8.1 represented by 2 Θ in the X-ray powder diffraction analysis spectrum. Diffusion angles of 8.8, 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0 and 15.2 ± 0.2°. That is, the crystal form G is characterized by X-ray powder diffraction pattern to include 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0, and 15.2 ± 0.2 ° 2 Θ Characteristic peak.
本发明提供的二甲氧基多西紫杉醇五分之一丙酮化物的晶型 G, 更多地， 包含在 X-射线粉末衍射分析谱图中由 2 Θ表示的 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 12.6、 12.9、 13.5、 14.3、 15.0、 15.2、 15.7、 16.3、 16.5、 17.1、 17.6、 17.9士 0.2°的衍射角。 即， 晶 型 G通过 X-射线粉末衍射图谱表征显示了位于 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 12.6、 12.9、 13.5、 14.3、 15.0、 15.2、 15.7、 16.3、 16.5、 17.1、 17.6、 17.9士 0.2° 2 Θ的特征峰。  The crystal form G of the diacetate docetaxel pentaacetate provided by the present invention is more, and includes 7.2, 7.4, 7.8, 8.1 represented by 2 Θ in the X-ray powder diffraction analysis spectrum. 8.8, 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0, 15.2, 15.7, 16.3, 16.5, 17.1, 17.6, 17.9 ± 0.2° diffraction angle. That is, the crystallization of the Form G by X-ray powder diffraction pattern shows that it is located at 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0, 15.2, 15.7, 16.3, 16.5, 17.1, 17.6, 17.9 ± 0.2 ° 2 Θ characteristic peak.
已经公开的卡巴他赛的晶型包括晶型八、 B、 C、 D、 E和 F, 其具 体数据 （2 Θ衍射角表示的特征峰） 为： 晶型 Α : 为国际申请 WO200480026128公开， 但未列出具体的值， 仅列出了其 XRPD图谱， 参见其公开的附图 1。 晶型 Β: 为国际申请 WO200980102389公开， 特 征峰为 7.3、 8.1、 9.8、 10.4、 11.1、 12.7、 13.1、 14.3、 15.4和 15.9士 0.2°。 晶型 C: 为国际申请 WO200980102389公开, 特征峰为 4.3、 6.8、 7.4、 8.7、 10.1、 11.1、 11.9、 12.3、 12.6和 13.1士 0.2°。 晶型 D: 为国际申请 WO200980102389公开， 特征峰为 3.9、 7.7、 7.8、 7.9、 8.6、 9.7、 10.6、The crystal forms of the already disclosed cabazitaxel include crystal forms VIII, B, C, D, E and F, the specific data (characteristic peaks represented by the diffraction angle of 2 )) are: crystalline form Α: disclosed for international application WO200480026128, but Specific values are not listed, only their XRPD maps are listed, see Figure 1 of which it is disclosed. Form Β: For the international application WO200980102389, the characteristic peaks are 7.3, 8.1, 9.8, 10.4, 11.1, 12.7, 13.1, 14.3, 15.4 and 15.9 ± 0.2°. Form C: disclosed for international application WO200980102389, with characteristic peaks of 4.3, 6.8, 7.4, 8.7, 10.1, 11.1, 11.9, 12.3, 12.6 and 13.1 ± 0.2°. Form D: disclosed for international application WO200980102389, with characteristic peaks of 3.9, 7.7, 7.8, 7.9, 8.6, 9.7, 10.6,
10.8、 11.1和 12.3士 0.2°。 晶型 E: 为国际申请 WO200980102389公开， 特征峰为 7.1、 8.1、 8.9、 10.2、 10.8、 12.5、 12.7(极其微弱的峰， 可以 忽略）、 13.2、 13.4和 13.9士 0.2°。 晶型 F: 为国际申请 WO200980102389 公开， 特征峰为 4.4、 7.2、 8.2、 8.8、 9.6、 10.2、 10.9、 11.2、 12.1和 12.3士 0.2。。 10.8, 11.1 and 12.3 ± 0.2°. Form E: As disclosed in the international application WO200980102389, the characteristic peaks are 7.1, 8.1, 8.9, 10.2, 10.8, 12.5, 12.7 (extremely weak peaks, negligible), 13.2, 13.4 and 13.9 ± 0.2°. Form F: For the international application WO200980102389, the characteristic peaks are 4.4, 7.2, 8.2, 8.8, 9.6, 10.2, 10.9, 11.2, 12.1 and 12.3 ± 0.2. .
通过比较， 晶型 C、 D和 F分别存在 4.3、 3.9和 4.4°的 2 Θ特征峰, 与本发明的结晶形式差异显著； 晶型 A虽然在文献中没有列出具体数 据，但从图谱上也可以明显看出不存在低于 8.5°的 2 Θ特征峰数据； 晶 型 B和 E的特征数据相对而言比较类似， 以士 0.2°的范围看， 绝大部分 数据一致， 包括 7.3与 7.1°、 8.1与 8.1°、 9.8与 10.2°、 11.1与 10.8°、 12.7 与 12.5°、 13.1与 13.2°、 14.3与 13.9° (每组前面为晶型 B的数据， 后面 为晶型 E的数据）， 两种晶型只有两个特征峰不一样， 分别是晶型 B的 10.4、 15.4°, 晶型 E的 8.9、 13.4°, 因而差异不像前面的几种晶型一样 显著， 需要仔细辨认。  By comparison, crystal forms C, D, and F have a characteristic peak of 2 Θ of 4.3, 3.9, and 4.4, respectively, which is significantly different from the crystalline form of the present invention; although crystal form A does not list specific data in the literature, it is from the map. It can also be clearly seen that there is no 2 Θ characteristic peak data below 8.5°; the characterization data of crystal forms B and E are relatively similar, and in the range of 0.2°, most of the data are consistent, including 7.3 and 7.1. °, 8.1 and 8.1°, 9.8 and 10.2°, 11.1 and 10.8°, 12.7 and 12.5°, 13.1 and 13.2°, 14.3 and 13.9° (data for crystal form B in front of each group, data for crystal form E followed) The two crystal forms have only two characteristic peaks, which are 10.4 and 15.4° of crystal form B and 8.9 and 13.4° of crystal form E. Therefore, the difference is not as significant as the previous crystal forms, and needs to be carefully identified.
本发明的 XRPD数据（2 Θ衍射角表示的特征峰）为 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 12.6、 12.9、 13.5、 14.3、 15.0、 15.2。， 与晶型 B和 E最显著的区别是 2 Θ衍射角在 10以下的部分， 包括 7.2、 7.4、 7.8、 8.1、 8.8、 9.8°, 特别是在 7〜8之间出现密集的指紋区， 除此 之外的衍射角与晶型 B和 E比较一致， 包括： 10.2、 10.4、 11.1、 12.6、 The XRPD data of the present invention (characteristic peaks represented by the diffraction angle of 2 Θ) are 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0, 15.2. The most significant difference from Forms B and E is the portion of the 2 Θ diffraction angle below 10, including 7.2, 7.4, 7.8, 8.1, 8.8, 9.8°, especially between 7 and 8 where dense fingerprint areas appear. The diffraction angles other than this are consistent with Forms B and E, including: 10.2, 10.4, 11.1, 12.6,
12.9、 14.3°中的部分或多个。 Some or more of 12.9, 14.3°.
本发明提供的二甲氧基多西紫杉醇一丙酮化物的稳定转化物的 制备方法， 包括： 将二甲氧基多西紫杉醇（卡巴他赛）一丙酮化物于 真空条件下， 在干燥剂存在或不存在的条件下， 40〜60°C加热 24〜120 小时。 其中， 所述加热时间优选 24〜96小时， 更优选 30〜96小时， 最优 选 48〜96小时。 The invention provides a method for preparing a stable transformant of dimethoxy docetaxel monoacetonate, comprising: dissolving dimethoxy docetaxel (carbataxel) monoacetonate under vacuum in the presence of a desiccant or In the absence of the condition, heat at 40~60 °C for 24~120 hours. The heating time is preferably 24 to 96 hours, more preferably 30 to 96 hours, and most preferably 48 to 96 hours.
当加热时间为 24小时时， 得到的是二甲氧基多西紫杉醇二分之 一丙酮化物。 也就是说， 本发明提供的二甲氧基多西紫杉醇二分之一 丙酮化物的制备方法， 包括： 将二甲氧基多西紫杉醇（卡巴他赛）一 丙酮化物于真空条件下， 在干燥剂存在或不存在的条件下， 40〜60°C 加热 24小时。  When the heating time was 24 hours, one diacetate of dimethoxydosidicol was obtained. That is, the preparation method of the dimethoxy docetaxel divalent acetone of the present invention comprises: dimethoxy-docetaxel (carbataxel)-acetonate under vacuum, drying Heat at 40~60 ° C for 24 hours in the presence or absence of the agent.
当加热时间为 48〜96小时时，得到的是二甲氧基多西紫杉醇五分 之一丙酮化物， 为结晶形式， 即上述晶型 G。 也就是说， 本发明提供 的二甲氧基多西紫杉醇五分之一丙酮化物（也就是晶型 G )的制备方 法， 包括： 将二甲氧基多西紫杉醇（卡巴他赛）一丙酮化物于真空条 件下， 在干燥剂存在或不存在的条件下， 40〜60° 加热48〜96小时。  When the heating time is 48 to 96 hours, a pentoxide of one-fifth of dimethoxy docetaxel is obtained, which is a crystalline form, i.e., the above-mentioned crystal form G. That is, the preparation method of the diacetate docetaxel penta acetonide (that is, the crystal form G) provided by the present invention comprises: dimethoxy docetaxel (carbataxel) monoacetonate Under vacuum conditions, in the presence or absence of a desiccant, heat at 40 to 60 ° for 48 to 96 hours.
上述制备方法中， 加热温度优选 55 °C。 即在二甲氧基多西紫杉 醇二分之一丙酮化物和二甲氧基多西紫杉醇五分之一丙酮化物的制 备过程中， 温度均可优选 55 °C。  In the above production method, the heating temperature is preferably 55 °C. That is, in the preparation of diacetate docetaxel acetonide and dimethoxy docetaxel penta acetonate, the temperature may preferably be 55 °C.
上述制备方法中， 干燥剂可以选择无水氯化钙或五氧化二磷， 优 选无水氯化钙。  In the above preparation method, the desiccant may be selected from anhydrous calcium chloride or phosphorus pentoxide, preferably anhydrous calcium chloride.
根据工作环境， 可以随时停止加热， 加热时间累计达到上述范围 即可。在停止加热的间歇可以不必为此真空条件，优选保持真空条件。  According to the working environment, the heating can be stopped at any time, and the heating time can be accumulated to the above range. It is not necessary to be a vacuum condition for the intermittent heating stop, and it is preferred to maintain the vacuum condition.
本发明克服了现有技术中卡巴他赛一丙酮化物不稳定的缺点，通 过简单的处理即能找到二甲氧基多西紫杉醇（卡巴他赛）一丙酮化物 的稳定转化物。本发明制备得到的产物， 能在较为苛刻的条件下持续 很长时间， 状态并不发生变化， 体现了产物较好的稳定性； 而现有的 卡巴他赛一丙酮化物在类似的条件下持续极短时间即发生了转换，说 明十分不稳定。  The present invention overcomes the shortcomings of the prior art cabazitaxel-acetonate instability, and a stable conversion of dimethoxy docetaxel (cabbataxel) monoacetonate can be found by simple treatment. The product prepared by the invention can last for a long time under relatively harsh conditions, the state does not change, and the product has good stability; and the existing cabazitaxel-acetonate continues under similar conditions. The conversion occurred in a very short time, indicating that it is very unstable.
本发明制备方法简单，不需要制备出无水晶型就能得到满足药学 需要的稳定产物 （尤其是五分之一丙酮化物及其结晶形式）； 不需要 长时间高温处理， 使与温度相关的杂质含量降至最低， 保证了产品质 量， 进而有利于患者健康。 The preparation method of the invention is simple, and the stable product (especially one-fifth acetonide and its crystalline form) satisfying the pharmaceutical requirement can be obtained without preparing the crystal-free type; Long-term high temperature treatment minimizes the temperature-related impurities, ensuring product quality and thus contributing to patient health.
本发明的五分之一丙酮化物与已经上巿的卡巴他赛原料药相比， 具有更高的稳定性， 以其为原料药制成的制剂的质量更佳， 使得成本 间接降低 （紫杉烷类抗癌药物价格极其昂贵）， 而且活性原料中包含 的丙酮更少， 因而具有更高的安全性。 附图说明  The one-fifth of the acetonide of the present invention has higher stability than the above-mentioned cappastamine drug substance, and the quality of the preparation made of the drug substance is better, and the cost is indirectly lowered (yew Alkane anticancer drugs are extremely expensive, and the active feedstock contains less acetone and is therefore more safe. DRAWINGS
图 1为无定形卡巴他赛原料药的 HNMR谱。  Figure 1 is an HNMR spectrum of an amorphous cabazitaxel bulk drug.
图 2为按照实施例 1得到的卡巴他赛一丙酮化物的 HNMR谱。 图 3为卡巴他赛一丙酮化物在真空、 55°C下处理 24小时的 HNMR 谱， 谱中丙酮含量为 3.2%, 即含有二分之一丙酮分子。  Figure 2 is an H NMR spectrum of the cabazitaxel monoacetonate obtained in accordance with Example 1. Figure 3 shows the H NMR spectrum of cabazitaxel-acetonate treated under vacuum at 55 ° C for 24 hours with a acetone content of 3.2%, i.e. containing one-half of acetone.
图 4为卡巴他赛一丙酮化物在真空、 55°C下处理 48小时的 HNMR 谱， 谱中丙酮含量为 1.3%, 即含有五分之一丙酮分子。  Figure 4 shows the H NMR spectrum of cabazitaxel-acetonate treated under vacuum at 55 ° C for 48 hours. The acetone content in the spectrum is 1.3%, i.e., contains one-fifth of acetone molecules.
图 5为卡巴他赛一丙酮化物在真空、 55°C下处理 72小时的 HNMR 谱， 谱中丙酮含量为 1.3%, 即仍然含有五分之一丙酮分子。  Figure 5 shows the H NMR spectrum of cabazitaxel-acetonate treated under vacuum at 55 ° C for 72 hours with an acetone content of 1.3%, i.e. still containing one-fifth of acetone molecules.
图 6为卡巴他赛一丙酮化物在真空、 55°C下处理 72小时的 TGA 谱， 谱中丙酮含量为 1.3%, 即仍然含有五分之一丙酮分子。  Figure 6 shows the TGA spectrum of cabazitaxel-acetonate treated under vacuum at 55 ° C for 72 hours. The acetone content in the spectrum is 1.3%, which still contains one-fifth of acetone molecules.
图 7为卡巴他赛一丙酮化物在真空、 55°C下处理 72小时的 XPRD 谱。  Figure 7 shows XPRD spectra of cabazitaxel-acetonate treated under vacuum at 55 °C for 72 hours.
图 8为卡巴他赛一丙酮化物在真空、 55°C下处理 96小时的 HNMR 谱， 谱中丙酮含量为 1.3%, 即仍然含有五分之一丙酮分子。  Figure 8 shows the H NMR spectrum of a kappataxel-acetonate treated under vacuum at 55 ° C for 96 hours. The acetone content in the spectrum was 1.3%, i.e., still contained one-fifth of acetone molecules.
图 9为按照实施例 4得到的溶液于 25°C放置 6个月后测得的 HPLC图谱。 具体实施方式  Figure 9 is a HPLC chart of the solution obtained in accordance with Example 4 after standing at 25 ° C for 6 months. detailed description
以下通过各实施例进一步说明本发明的内容，但不应理解为对本 发明的限制。 在不背离本发明精神和实质的情况下， 对本发明方法、 步骤或条件所作的修改或替换， 均属于本发明的范围。 若未特别指明，本发明未描述的实验操作方法和条件均为本领域 的常规选择。 The contents of the present invention are further illustrated by the following examples, but are not to be construed as limiting the invention. Modifications or substitutions of the methods, steps or conditions of the invention are intended to be within the scope of the invention. Experimental methods and conditions not described in the present invention are conventional choices in the art unless otherwise specified.
本发明釆用 BRUKER D8 ADVANCE X射线粉末衍射仪，测定条 件： CuKal 辐射（ λ =1.5406Α ), 管压 45 kV, 2 6扫描范围 5〜50 ° , 步长 0.015 ° , X射线粉末衍射实验数据以 2 Θ衍射角体现。 X射线粉 末衍射图谱的理论探讨可见于 "X 射线衍射过程 (X-ray diffraction procedures)" , Η. P. Klug 和 L. E. Alexander, J. Wiley, New York (1974)。  The invention adopts BRUKER D8 ADVANCE X-ray powder diffractometer, and the measurement conditions are: CuKal radiation (λ = 1.5406 Α), tube pressure 45 kV, 26 6 scanning range 5~50 °, step length 0.015 °, X-ray powder diffraction experimental data Reflected at a diffraction angle of 2 。. A theoretical discussion of X-ray powder diffraction patterns can be found in "X-ray diffraction procedures", Η. P. Klug and L. E. Alexander, J. Wiley, New York (1974).
本发明的无定形卡巴他赛原料参考中国专利申请 CN 96192884 所述的方法制备， 原料质量由 HPLC 确定： 含量 >99% , 单杂小于 0.15%。 对其进行检测分析， 得到如图 1所示的 HNMR谱， 谱中可以 清晰看出不含水分和有机溶剂。  The amorphous cabazitaxel material of the present invention is prepared by the method described in Chinese patent application CN 96192884, and the quality of the raw material is determined by HPLC: the content is >99%, and the single impurity is less than 0.15%. It was analyzed and analyzed to obtain an HNMR spectrum as shown in Fig. 1, and it was clearly observed that the moisture and the organic solvent were not contained in the spectrum.
实施例 1: 卡巴他赛一丙酮化物的制备 Example 1: Preparation of Cabazitaxel-Acetone
参考国际申请 WO200480026128中实施例 1公开的方法，将 2mL 纯净水加入到 500mg卡巴他赛在 4.8mL丙酮的溶液中，然后加入 5mg 卡巴他赛在 0.05mL水和 0.05mL丙酮的悬浮液种晶。 将混合物搅拌 16h后，加入 3.6mL纯净水，然后搅拌 lh,过滤，用 lmL丙酮和 1.3mL 水的混合液洗滤饼。 然后在真空干燥箱中， 以油泵减压干燥产品， 在 55 °C下 4h得到产品 460mg。 NMR显示丙酮含量为 7.3%(参见附图 2 ), 与国际申请 WO 200480026128保护的卡巴他赛一丙酮溶剂化物包含 的丙酮数据相当 （其测定的丙酮含量均值为 7%左右， 理论值为 6.5% )。  Referring to the method disclosed in Example 1 of International Application WO200480026128, 2 mL of purified water was added to a solution of 500 mg of cabazitaxel in 4.8 mL of acetone, followed by seeding of a suspension of 5 mg of cabazitaxel in 0.05 mL of water and 0.05 mL of acetone. After the mixture was stirred for 16 hours, 3.6 mL of purified water was added, then stirred for 1 hour, filtered, and the filter cake was washed with a mixture of 1 mL of acetone and 1.3 mL of water. Then, in a vacuum drying oven, the product was dried under reduced pressure with an oil pump, and 460 mg of the product was obtained at 55 ° C for 4 hours. NMR showed an acetone content of 7.3% (see Figure 2), comparable to the acetone data contained in the Kabutstatin-acetone solvate protected by International Application WO 200480026128 (the average acetone content determined was around 7%, the theoretical value was 6.5%). ).
实施例 2: 卡巴他赛二分之一丙酮化物的制备 Example 2: Preparation of cabazitaxel one-half acetone
按照实施例 1的方法获得卡巴他赛一丙酮化物后，再在真空干燥箱 中以油泵减压干燥产品， 在 55 °C下处理 24h得到目标产品 （即卡巴他 赛二分之一丙酮化物）， NMR显示丙酮含量为 3.2% (参见附图 3 )。  After obtaining the cabazitaxel-acetonate according to the method of Example 1, the product was dried under reduced pressure in a vacuum drying oven by an oil pump, and treated at 55 ° C for 24 hours to obtain a target product (ie, one-part acetone of cabazitaxel). , NMR showed an acetone content of 3.2% (see Figure 3).
从本实施例也可以看出： 现有的卡巴他赛一丙酮化物在制备的条 件下处理一段时间即发生了转换， 说明其十分不稳定。 实施例 3: 卡巴他赛五分之一丙酮化物的制备 It can also be seen from this example that the existing cabazitaxel-acetonate is converted under the conditions of preparation for a period of time, indicating that it is very unstable. Example 3: Preparation of one-fifth acetone of cabazitaxel
方法一：  method one:
按照实施例 2的方法获得卡巴他赛二分之一丙酮化物后，然后在真 空干燥箱中以油泵减压干燥产品，在 55 °C下继续处理 24h(即共计 48h ) 可以得到目标产品 （即卡巴他赛五分之一丙酮化物， 为结晶形式）， NMR显示丙酮含量为 1.3% (参见附图 4 )。  After obtaining one-half of the acetonide of cabazitaxel according to the method of Example 2, the product was dried under reduced pressure in an air drying oven, and the treatment was continued at 55 ° C for 24 hours (ie, 48 hours in total) to obtain the target product (ie, One-fifth of the acetonide in cabazitaxel, in crystalline form, NMR showed an acetone content of 1.3% (see Figure 4).
方法二：  Method Two:
按照上述方法一获得的卡巴他赛五分之一丙酮化物， 其继续在真 空干燥箱中以油泵减压干燥产品， 在 55 °C处理 24h (即共计 72h )无变 化， 仍然得到目标产品。 NMR显示丙酮含量为 1.3% (参见附图 5 ); TGA显示丙酮含量为 1.3% (参见附图 6 ); XPRD: 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 12.6、 12.9、 13.5、 14.3、 15.0、 15.2、 15.7、 16.3、 16.5、 17.1、 17.6、 17.9士 0.2°的特征峰（ 2 Θ ) (参见附图 7 )。  According to the above method 1, one-fifth of the effervescent of cabazitaxel was continuously dried in a vacuum drying oven with an oil pump, and the product was treated at 55 ° C for 24 h (i.e., total 72 h) without change, and the target product was still obtained. NMR showed an acetone content of 1.3% (see Figure 5); TGA showed an acetone content of 1.3% (see Figure 6); XPRD: 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0, 15.2, 15.7, 16.3, 16.5, 17.1, 17.6, 17.9 ± 0.2° characteristic peak ( 2 Θ ) (see Figure 7).
在图 7中， 主要的峰信息如下表所示:  In Figure 7, the main peak information is shown in the following table:
Figure imgf000012_0001
10 11.922 7.41763 0.6
Figure imgf000012_0001
10 11.922 7.41763 0.6
11 12.662 6.98523 23.411 12.662 6.98523 23.4
12 12.993 6.80843 21.312 12.993 6.80843 21.3
13 13.515 6.54624 3.413 13.515 6.54624 3.4
14 14.327 6.17728 13.114 14.327 6.17728 13.1
15 15.008 5.89845 4.215 15.008 5.89845 4.2
16 15.279 5.79448 4.516 15.279 5.79448 4.5
17 15.797 5.60536 11.417 15.797 5.60536 11.4
18 16.323 5.42614 8.818 16.323 5.42614 8.8
19 16.518 5.36234 5.519 16.518 5.36234 5.5
20 17.170 5.16021 9.220 17.170 5.16021 9.2
21 17.606 5.03338 9.921 17.606 5.03338 9.9
22 17.948 4.93826 3.722 17.948 4.93826 3.7
23 18.157 4.88200 3.723 18.157 4.88200 3.7
24 18.510 4.78949 18.024 18.510 4.78949 18.0
25 18.798 4.71681 9.225 18.798 4.71681 9.2
26 19.176 4.62466 1.926 19.176 4.62466 1.9
27 19.791 4.48232 10.727 19.791 4.48232 10.7
28 20.440 4.34142 5.728 20.440 4.34142 5.7
29 21.082 4.21076 1.829 21.082 4.21076 1.8
30 21.917 4.05213 8.330 21.917 4.05213 8.3
31 22.609 3.92956 6.931 22.609 3.92956 6.9
32 22.959 3.87054 2.932 22.959 3.87054 2.9
33 24.005 3.70415 3.233 24.005 3.70415 3.2
34 24.340 3.65401 3.834 24.340 3.65401 3.8
35 24.832 3.58271 1.335 24.832 3.58271 1.3
36 25.403 3.50342 5.236 25.403 3.50342 5.2
37 26.198 3.39891 4.0 本发明所述的卡巴他赛五分之一丙酮化物的结构可以通过核磁 共振和 TGA确定，分子中所含的丙酮通过核磁共振方法和 TGA可以获 得良好的定性和定量， 而且这两种方法具有良好的相关性。 37 26.198 3.39891 4.0 The structure of the one-fibrate acetonide of cabazitaxel according to the present invention can be determined by nuclear magnetic resonance and TGA, and the acetone contained in the molecule can be obtained by nuclear magnetic resonance method and TGA. Good qualitative and quantitative, and the two methods have a good correlation.
方法三： Method three:
按照上述方法二获得的卡巴他赛五分之一丙酮化物的晶型 G, 其 继续在真空干燥箱中以油泵减压干燥产品， 在 55 °C处理 24h (即共计 96h )仍无变化，即仍然得到目标产品， NMR显示丙酮含量为 1.3% (参 见附图 8 )。  According to the above method 2, the crystal form G of one-fifth of the effervescent of cabazitaxel is continuously dried in a vacuum drying oven by an oil pump, and the product is still unchanged after being treated at 55 ° C for 24 hours (ie, 96 hours in total), that is, The target product was still obtained, and NMR showed an acetone content of 1.3% (see Figure 8).
用方法三得到的卡巴他赛五分之一丙酮化物晶型 G的 XPRD谱， 与图 7基本一致。  The XPRD spectrum of the one-fibrous acetonate form G of cabazitaxel obtained by the third method is substantially the same as that of Fig. 7.
方法四： Method four:
将如实施例 1的方法获得的卡巴他赛一丙酮化物继续置于真空干 燥箱中， 在无水氯化钙存在下， 以油泵减压获得真空， 然后在 40°C干 燥 120h可以得到卡巴他赛五分之一丙酮化物 （为结晶形式， 即晶型 G ), 其 XPRD谱与图 7基本一致， HNMR图谱与图 4、 5和 8基本一致。 方法五：  The cabazitaxel monoacetonate obtained by the method of Example 1 was continuously placed in a vacuum drying oven, and vacuum was obtained by decompression with an oil pump in the presence of anhydrous calcium chloride, and then dried at 40 ° C for 120 hours to obtain a kappa. One-fifth of the acetonide (in crystalline form, ie, Form G), its XPRD spectrum is substantially identical to that of Figure 7, and the HNMR spectrum is substantially identical to Figures 4, 5 and 8. Method five:
将如实施例 1 的方法获得的卡巴他赛一丙酮化物继续置于真空 干燥箱中， 在无水氯化钙存在下， 以油泵减压获得真空， 然后在 60°C 干燥 48h可以得到卡巴他赛五分之一丙酮化物（为结晶形式， 即晶型 G ), 其 XPRD谱与图 Ί基本一致， HNMR图谱与图 4、 5和 8基本一 实施例 3说明：本发明制备得到的产物，能在较为苛刻的条件下， 持续很长时间， 但状态并不发生变化， 体现了较好的稳定性。  The cabazitaxel-acetonate obtained as in the method of Example 1 was continuously placed in a vacuum drying oven, and a vacuum was obtained by decompression with an oil pump in the presence of anhydrous calcium chloride, followed by drying at 60 ° C for 48 hours to obtain a kappa. One-fifth of the acetonide (in crystalline form, ie, crystalline form G), the XPRD spectrum is substantially identical to that of the figure, and the HNMR spectrum is substantially the same as that of FIGS. 4, 5 and 8 to illustrate the product prepared by the present invention. Under a more severe condition, it lasts for a long time, but the state does not change, showing good stability.
在实施例 1公开方法的基础上，并没有文献公开他人继续进行反 应从而得到卡巴他赛含丙酮的稳定转化物。 发明人在现有技术（得到 产品稳定性欠缺）的基础上进行继续研究和改进， 排除大量干扰因素 (其中会产生大量的不稳定的转化物），经过长期和反复试验的摸索， 最终确定了本发明。 实施例 4 On the basis of the method disclosed in Example 1, there is no disclosure in the literature that others continue to react to obtain a stable conversion of cabazitaxel containing acetone. The inventors continued research and improvement on the basis of the prior art (lack of product stability), and eliminated a large number of interfering factors (which generate a large number of unstable transformants). After long-term and trial and error exploration, the inventors finally determined. this invention. Example 4
卡巴他赛的上巿产品 （商品名： JEVTANA )为 60 mg/1.5 mL的 原始溶液： 包含 60 mg的卡巴他赛一丙酮化物及 1.5 mL的聚山梨醇 酯 80。 在给患者用药前需要经过两步稀释， 第一步为： 使用 5.7 mL 的 13% ( w/w ) 的乙醇水溶液将原始溶液稀释为 10 mg/mL的混合溶 液； 第二步为： 将第一步的稀释溶液以注射剂转移至 250 mL的 0.9% 的氯化钠溶液或 5%的葡萄糖溶液中待用。  The capsaid product of Cabazitaxel (trade name: JEVTANA) is a 60 mg/1.5 mL original solution: contains 60 mg of cabazitaxel-acetonate and 1.5 mL of polysorbate 80. A two-step dilution is required before administration to the patient. The first step is: Dilute the original solution to a 10 mg/mL mixed solution using 5.7 mL of 13% (w/w) aqueous ethanol solution; the second step is: The one-step dilution solution is transferred to 250 mL of 0.9% sodium chloride solution or 5% glucose solution for injection.
将实施例 3方法二得到的原料药产品以聚山梨醇酯 80为溶剂， 也可以顺利地制备得到 60 mg/1.5 mL浓度的溶液。 该溶液于 25°C放 置 6个月后， HPLC显示产品非常稳定（见附图 9 ), 其分别经过与 JEVTANA相同的两步稀释后也能够顺利得到完全相同的相应产品。  The raw material drug product obtained in the second method of the third embodiment was prepared by using the polysorbate 80 as a solvent, and a solution having a concentration of 60 mg/1.5 mL was also smoothly prepared. After the solution was allowed to stand at 25 ° C for 6 months, HPLC showed that the product was very stable (see Figure 9), and the same two-step dilutions as JEVTANA were used to obtain the exact same product.
波长 =230 nm, 附图 9相关信息如下表所示:  Wavelength = 230 nm, the relevant information in Figure 9 is shown in the following table:
Figure imgf000015_0001
Figure imgf000015_0001
工业实用性  Industrial applicability
本发明提供的二甲氧基多西紫杉醇（卡巴他赛）丙酮化物， 以及 相应的结晶形式具有更高的稳定性，利用它们作为原料药制成具有抗 癌和抗白血病功效的药物制剂， 更便于产品的质量控制， 会使得制剂 产品有效期长、 质量更佳； 同时， 活性原料中包含的丙酮更少， 因而 具有更高的安全性。  The dimethoxy docetaxel (carbataxel) acetonide provided by the invention, and the corresponding crystalline form have higher stability, and use them as a raw material medicine to prepare a pharmaceutical preparation having anticancer and anti-leukemia effects, Facilitating the quality control of the product will make the preparation product have a longer effective period and better quality; at the same time, the active raw material contains less acetone and thus has higher safety.

Claims

权 利 要 求 书 claims
1、 二甲氧基多西紫杉醇一丙酮化物的 , 结构式如下: 1. The structural formula of dimethoxy docetaxel monoacetonate is as follows:
Figure imgf000016_0001
Figure imgf000016_0001
其中， X=l/2或 1/5。 Among them, X=l/2 or 1/5.
2、 根据权利要求 1所述二甲氧基多西紫杉醇一丙酮化 2. Monoacetonation of dimethoxy docetaxel according to claim 1
, 其特征在于， 当 X=l/5时， 结构式如下： , which is characterized in that when X=l/5, the structural formula is as follows:
' CH,
Figure imgf000016_0002
'CH,
Figure imgf000016_0002
'、 权利要求 2所述二甲氧基多西紫杉醇一丙酮化物的转化物的 ', the conversion product of dimethoxy docetaxel-acetonate described in claim 2
'晶形: K , 其包含在 X-射线粉末衍射分析谱图中由 2 Θ表示的 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 11.1、 13.5和 15.0士 0.2°的衍射角。 'Crystal form: K, which contains diffraction angles of 7.2, 7.4, 7.8, 8.1, 8.8, 9.8, 11.1, 13.5 and 15.0±0.2° represented by 2Θ in the X-ray powder diffraction analysis spectrum.
4、 权利要求 2所述二甲氧基多西紫杉醇一丙酮化物的转化物的 结晶形式，其包含在 X-射线粉末衍射分析图谱图中由 2 Θ表示的 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 13.5、 14.3、 15.0和 15.2 4. The crystalline form of the conversion product of dimethoxy docetaxel monoacetonate according to claim 2, which contains 7.2, 7.4, 7.8, 8.1, 8.8 represented by 2Θ in the X-ray powder diffraction analysis pattern. , 9.8, 10.2, 10.4, 11.1, 13.5, 14.3, 15.0 and 15.2
5、 权利要求 2所述二甲氧基多西紫杉醇一丙酮化物的转化物的 结晶形式， 其包含在 X-射线粉末衍射分析谱图中由 2 Θ表示的 7.2、 7.4、 7.8、 8.1、 8.8、 9.8、 10.2、 10.4、 11.1、 12.6、 12.9、 13.5、 14.3、 15.0和 15.2士 0.2°^ fe 5. The crystalline form of the conversion product of dimethoxy docetaxel monoacetonide according to claim 2, which contains 7.2, 7.4, 7.8, 8.1, and 8.8 represented by 2Θ in the X-ray powder diffraction analysis spectrum. , 9.8, 10.2, 10.4, 11.1, 12.6, 12.9, 13.5, 14.3, 15.0 and 15.2±0.2°^ fe
6、 权利要求 1或 2所述二甲氧基多西紫杉醇一丙酮化物的转化 物的制备方法，包括： 将二甲氧基多西紫杉醇一丙酮化物于真空条件 下， 在干燥剂存在或不存在的条件下， 40〜60°C加热 24〜120小时。 6. The preparation method of the conversion product of dimethoxy docetaxel-acetonate according to claim 1 or 2, comprising: converting dimethoxy docetaxel-acetonate under vacuum conditions, in the presence or absence of a desiccant Under the conditions of presence, heat at 40~60°C for 24~120 hours.
7、 根据权利要求 6所述的制备方法， 其特征在于， 加热时间为 24〜96小时。 7. The preparation method according to claim 6, characterized in that the heating time is 24 to 96 hours.
8、 根据权利要求 6或 7所述的制备方法， 其特征在于， 加热时 间为 24小时， 得到的二甲氧基多西紫杉醇一丙酮化物的转化物的结 构式如下： 8. The preparation method according to claim 6 or 7, characterized in that the heating time is 24 hours, and the obtained transformation product of dimethoxydocetaxel-acetonide has the following structural formula:
Figure imgf000017_0001
Figure imgf000017_0001
9、 根据权利要求 6或 7所述的制备方法， 其特征在于， 加热时 间为 48〜96小时，得到的二甲氧基多西紫杉醇一丙酮化物的转化物的 结构式如下： 9. The preparation method according to claim 6 or 7, characterized in that the heating time is 48 to 96 hours, and the obtained transformation product of dimethoxydocetaxel-acetonide has the following structural formula:
Figure imgf000017_0002
Figure imgf000017_0002
10、权利要求 3〜5任意一项所述二甲氧基多西紫杉醇一丙酮化物 转化物的结晶形式的制备方法， 包括： 将二甲氧基多西紫杉醇一丙酮 化物于真空条件下， 在干燥剂存在或不存在的条件下， 40〜60°C加热 48〜96小时。 10. A method for preparing the crystalline form of the dimethoxy docetaxel-acetonate conversion product according to any one of claims 3 to 5, comprising: placing the dimethoxy docetaxel-acetonate conversion product under vacuum conditions, Heating at 40~60°C for 48~96 hours with or without desiccant.
11、根据权利要求 6〜10任意一项所述的制备方法， 其特征在于, 加热温度为 55 °C。 11. The preparation method according to any one of claims 6 to 10, characterized in that, The heating temperature is 55 °C.
12、根据权利要求 6〜10任意一项所述的制备方法， 其特征在于， 所述干燥剂为： 无水氯化钙或五氧化二磷。 12. The preparation method according to any one of claims 6 to 10, characterized in that the desiccant is: anhydrous calcium chloride or phosphorus pentoxide.
PCT/CN2013/078847 2013-07-04 2013-07-04 Stable transformation product of dimethoxy docetaxel mono-acetonate and crystalline forms thereof, and methods for preparation of same WO2015000165A1 (en)

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WO2009115655A2 (en) * 2008-01-17 2009-09-24 Aventis Pharma S.A. Crystalline forms of dimethoxy docetaxel and methods for preparing same
WO2013034979A2 (en) * 2011-09-09 2013-03-14 Scinopharm Taiwan, Ltd. Crystalline forms of cabazitaxel
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WO2009115655A2 (en) * 2008-01-17 2009-09-24 Aventis Pharma S.A. Crystalline forms of dimethoxy docetaxel and methods for preparing same
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