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Crystal forms of cabazitaxel and preparation method thereof

A technology of cabazitaxel and forms, applied in organic chemical methods, medical preparations containing active ingredients, pharmaceutical formulations, etc., can solve the differences in microscopic crystal structures that affect the processing performance, appearance, physical and chemical properties and biological activities of preparations and other problems, to achieve the effects of weak toxicity, good storage and handling stability, and excellent performance

Active Publication Date: 2012-10-24
重庆兴泰濠制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Different crystal forms of the same compound have the same chemical composition but different microscopic crystal structures, which lead to differences in their appearance, physicochemical properties and biological activities
These characteristics directly affect the preparation performance of the drug, and will affect the stability, solubility and bioavailability of the drug, which in turn will affect the quality, safety, effectiveness and application of the drug

Method used

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  • Crystal forms of cabazitaxel and preparation method thereof
  • Crystal forms of cabazitaxel and preparation method thereof
  • Crystal forms of cabazitaxel and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Add 10 g of cabazitaxel monohydrate to 300 mL of ethyl acetate and heat to dissolve, concentrate until a small amount of crystals precipitate out, crystallize overnight at 0-5°C, filter with suction, and vacuum-dry the filter cake at a temperature of 50-60°C to obtain 9.4 g of cabazitaxel ethyl acetate compound form type J crystal. HPLC detection purity ≥ 99.76%, GC detection of its ethyl acetate residue is 95000ppm, X-ray powder diffraction spectrum, infrared spectrum spectrum, TGA spectrum and DSC spectrum respectively see figure 1 , figure 2 , image 3 , Figure 4 .

Embodiment 2

[0053] Add 10 g of cabazitaxel to 300 mL of methyl formate and heat to dissolve, concentrate until a small amount of crystals precipitate out, crystallize overnight at 0-5°C, filter with suction, and vacuum-dry the filter cake at a temperature of 50-60°C to obtain 9.0 g of cabazitaxel The form of methyl tacetidine carboxylate is crystal J. The purity detected by HPLC is ≥99.78%, and the residual methyl formate is 85400ppm detected by GC.

Embodiment 3

[0055] Add 5g of cabazitaxel ethyl acetate into 75mL of ethanol and stir to dissolve, then quickly add 150mL of purified water dropwise, cool down to 8°C after the addition, let stand for 2h and then filter, wash the filter cake with 200mL of purified water for several times, The filter cake was dried under reduced pressure at 60°C for 12 hours to obtain 4.6 g of white crystalline cabazitaxel monohydrate. HPLC detection purity ≥ 99.87%, Karl Fischer method determination of water content of 2.4%, its X-ray powder diffraction spectrum, infrared spectrum, TGA spectrum and DSC spectrum are shown in Figure 5 , Figure 6 , Figure 7 , Figure 8 .

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Abstract

The invention relates to the field of medicinal chemistry, and discloses three crystal forms of cabazitaxel, i.e., an ester compound crystal form J of cabazitaxel, a hydrate crystal form G of cabazitaxel and a cabazitaxel crystal form I, and a preparation method of a novel crystal form of cabazitaxel. The novel cabazitaxel form has superior performance on the aspects of oral absorptivity, activation of metabolism and suppression of mitosis and interval cell function of cells, is weak in toxicity, has high storing and treating stability, and can be applied to preparation of a medicament for treating prostatitis.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new crystal form of cabazitaxel and a preparation method thereof. Background technique [0002] Cabazitaxel, the English name is Cabazitaxel, the chemical name is 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1-hydroxy-7β, 10β-dimethoxy-9-oxo (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate of -11-taxene-13α-yl alcohol, a kind developed by Sanofi-aventis company in France Chemically semi-synthesized taxane-like small molecule compounds, and a second-line drug for prostate cancer that was approved for marketing in the United States in June 2010. The structure is shown in formula I: [0003] [0004] The anti-cancer mechanism and characteristics of cabazitaxel are similar to those of docetaxel, and it belongs to anti-microtubule drugs. Cabazitaxel binds to tubulin, promotes its assembly into microtubules, and at the same time prevents the disassembly of these assembl...

Claims

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Application Information

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IPC IPC(8): C07D305/14A61P35/00
CPCC07D305/14A61K31/337A61P13/08A61P35/00C07B2200/13
Inventor 李靖姚全兴
Owner 重庆兴泰濠制药有限公司
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