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Jevtana solvate and preparation method and application thereof

A technology of cabazitaxel and solvate, applied in the field of drug synthesis, can solve the problems of no reported solvate preparation method, poor stability of cabazitaxel anhydrous, uncharacterized solvate, etc., and achieves strong practical value and good stability. , the effect of weak hygroscopicity

Inactive Publication Date: 2014-05-21
SHANGHAI ACEBRIGHT PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] For cabazitaxel anhydrate, it will become the corresponding hydrate after being placed at different humidity for a period of time, and the water content obtained according to the humidity is also different. Therefore, the stability of cabazitaxel anhydrate is also relatively high. Difference
[0021] In addition, the patent WO2009 / 115655 also discloses the preparation of other non-alcoholic compounds of crystal form B, such as: dichloromethane, diisopropyl ether, n-propanol, isopropanol, toluene, methyl isobutyl ketone, tetrahydrofuran, Dimethylformamide, ethyl acetate, etc., however, the patent does not characterize the solvate, nor report the preparation method of the solvate

Method used

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  • Jevtana solvate and preparation method and application thereof
  • Jevtana solvate and preparation method and application thereof
  • Jevtana solvate and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Add 25.0g of cabazitaxel raw material (HPLC purity 99.1%) into 250mL of ethyl acetate, heat to 70°C, stir to dissolve completely; naturally cool to 40°C, keep warm and continue to stir for 8 hours to precipitate crystals; then cool down naturally to 25° C., kept stirring for 2 hours; filtered, the filter cake was washed with 20 mL of ethyl acetate, and vacuum-dried at 40° C. for 8 hours to obtain 25.4 g of cabazitaxel ethyl acetate, which contained 9.47% ethyl acetate (theoretical amount was 9.53%), and the HPLC purity was 99.6%.

[0079] The HNMR data are as follows: 1 H NMR (400MHz, CDCl 3 )δ8.11(d,J=7.4Hz,2H),7.62(t,J=7.4Hz,1H),7.51(t,J=7.7Hz,2H),7.45–7.38(m,4H),7.37– 7.31(m,1H),6.23(t,J=8.3Hz,1H),5.65(d,J=6.9Hz,1H),5.47(d,J=9.6Hz,1H),5.30(d,J=9.21 H),4.99(d,J=8.1Hz,1H),4.81(s,1H),4.64(s,1H),4.32(d,J=8.5Hz,1H),4.16(dt,J=14.3,7.8 Hz,3H),3.87(dd,J=10.7,6.4Hz,1H),3.83(d,J=7.0Hz,1H),3.47(s,4H),3.32(s,3H),2.77-2.66(m ,1H),2.38(s,3H),2.30(d,J=9.2Hz,2H),2.19(s,1H),2.06...

Embodiment 2

[0091] Add 10.0 g of cabazitaxel raw material (HPLC purity 98.5%) into 200 mL of ethyl acetate, heat to 60 ° C, stir to dissolve completely; naturally cool to 40 ° C, add 0.05 g of cabazitaxel ethyl acetate solvate as crystal and keep stirring for 5 hours to precipitate crystals; then naturally cool down to 20°C, keep stirring for 2 hours; filter, wash the filter cake with 20mL of ethyl acetate, and dry in vacuum at 40°C for 8 hours to obtain 10.3g of cabazitaxel Ethyl acetate, which contains 9.25% ethyl acetate, HPLC purity is 99.5%.

[0092] The HNMR data, PXRD spectrogram, DSC spectrogram and TGA spectrogram of the cabazitaxel solvate obtained in this embodiment are consistent with the spectrogram results obtained in Example 1 within the error range, and the stability test results are also consistent. It is consistent with the experimental results obtained in Example 1 within the error range.

Embodiment 3

[0094] Add 10.0g of cabazitaxel raw material (HPLC purity 85.3%) into 80mL ethyl acetate / tetrahydrofuran (5 / 1V / V), heat to 65°C, stir to dissolve completely; naturally cool to 50°C, add 0.1g of cabazitaxel Taxalate ethyl acetate solvate was used as crystal seed, kept stirring for 5 hours to precipitate crystals; then naturally cooled to 10°C, kept stirring for 2 hours; filtered, and the filter cake was washed with 20mL ethyl acetate / tetrahydrofuran (5 / 1V / V) Washing and vacuum drying at 40° C. for 8 hours to obtain 10.5 g of cabazitaxel ethyl acetate, which contained 9.07% ethyl acetate, and the HPLC purity was 99.6%.

[0095] The HNMR data, PXRD spectrogram, DSC spectrogram and TGA spectrogram of the cabazitaxel solvate obtained in this embodiment are consistent with the spectrogram results obtained in Example 1 within the error range, and the stability test results are also consistent. It is consistent with the experimental results obtained in Example 1 within the error rang...

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Abstract

The invention discloses a jevtana solvate and a preparation method and application thereof. The solvate is a crystalline formed by solvating jevtana and ethyl acetate, and contains ethyl acetate with the mass ratio of 8-10%. The jevtana solvate has the advantages of high stability and weak moisture absorption, and is beneficial to preparing preparations with the quality meeting a criterion. The preparation method has remarkable advantages of being simple to operate, stable in quality, high in yield, low in cost, energy saving and environmentally friendly, meets the industrial production requirement and has extremely strong practical value and wide application prospect.

Description

technical field [0001] The invention relates to a solvate of cabazitaxel and its preparation method and application, belonging to the technical field of drug synthesis. Background technique [0002] Prostate cancer is a common malignancy in men, often affecting older men, and is the second most common cancer in men in the United States after skin cancer. Cabazitaxel (trade name Jevtana), its chemical name is: 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy -9-Oxotaxane-11-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, Sanofi-Aventis (Sanofi-Aventis SA) developed a microtubule inhibitor in 1996, its specific chemical structure is as follows: [0003] In 2010, due to its excellent curative effect, Cabazitaxel was approved by the FDA for priority review and approval for marketing. It is used for patients with advanced prostate cancer who are ineffective or even aggravated by docetaxel. It is the preferred drug for the treatment of adva...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/14A61K31/337A61P35/00A61P35/02
CPCC07D305/14
Inventor 安晓霞余利兵杨勤刚任华森顾成龙郭茂君
Owner SHANGHAI ACEBRIGHT PHARMA CO LTD
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