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Preparation method of taxanes compound

A compound, the technology of docetaxel, which is applied in the field of preparation of taxane compounds, can solve the problems of many reaction steps and long reaction time, and achieve the effect of less reaction steps, short preparation time and improved purity

Active Publication Date: 2011-05-18
重庆兴泰濠制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In view of this, the purpose of the present invention is to provide a method for preparing the taxane compound cabazitaxel by one-step method for the existing taxane compound cabazitaxel preparation method with many reaction steps and long reaction time defects.

Method used

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  • Preparation method of taxanes compound

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preparation example Construction

[0032] A preparation method of taxane compounds shown in formula I is under the protection of nitrogen or argon, using docetaxel as a raw material, using benzene, alcohols, ketones or ethers as a solvent, and using 0.0083mL / s Add dimethyl sulfate 1 to 10 times the molar amount of docetaxel dropwise at a rate of ~0.05mL / s, and perform alkylation reaction at 10~60°C for 0.5~10h, during which time the reaction is controlled with a weakly alkaline organic solvent The pH value of the solution is 7-8. After the reaction is completed, water is added for crystallization, and the obtained crystal is the crude compound shown in formula I. Then dissolve the crude product of the compound shown in formula I with an alcohol compound, and then add water to precipitate the crystal, and the obtained crystal is the pure product of the compound shown in formula I, wherein, every 1 g of the crude product is dissolved by adding 10-20 mL of the compound of formula I, and adding 1-10 g of water to pr...

Embodiment 1

[0035] Embodiment 1: Preparation of taxane compounds of the present invention

[0036]Under nitrogen protection, put 25.8g (0.032mol) of docetaxel into a 500mL three-necked flask, add 258ml of acetone to raise the temperature to 35°C, stir the solution until it becomes clear, then add 10g (0.08mol) of sulfuric acid dropwise at a speed of 0.0083mL / s Dimethyl ester, while adding pyridine dropwise to maintain the pH value at 7-8 (the amount of pyridine is based on the pH value), after reacting for 5 hours at 40°C, add 60g of water to precipitate crystals, filter, and dry to obtain the crude product of the compound shown in formula I 24.1 g, yield 90.63%. The crude compound shown in Formula I was stirred and dissolved in 250 mL of methanol at 30°C to 40°C, then 25g of water was added to crystallize, the crystals were collected by filtration, and dried to obtain 22.2g of the compound shown in Formula I with a yield of 92.12% and a purity of 99.3 %.

[0037] NMR test results showe...

Embodiment 2

[0038] Embodiment 2: Preparation of taxane compounds of the present invention

[0039] Under the protection of argon, put 77.5g (0.096mol) of docetaxel into a three-necked flask, add 77.5mL of ethanol and raise the temperature to 35°C, stir the solution until it becomes clear, then add 12.6g (0.10mol) of docetaxel dropwise at a speed of 0.05mL / s ) dimethyl sulfate, while adding pyridine dropwise to maintain the pH value at 7 to 8 (the amount of pyridine is based on the pH value), after reacting for 10 hours at 10°C, add 300g of water, precipitate crystals, filter, and dry to obtain the compound of formula I The crude product was 74.9g, and the yield was 93.75%. The crude compound represented by formula I was dissolved in 1500 mL of ethanol, then crystallized by adding 700 g of water, the crystals were collected by filtration, and dried to obtain 46.5 g of the compound represented by formula I, with a yield of 93% and a purity of 99.2%.

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Abstract

The invention discloses a preparation method of a taxanes compound shown as the formula I in the specification, relating to the field of pharmaceutical chemistry. The preparation method comprises the following steps of: under the water isolating condition, with docetaxel as a raw material and benzene alcohol, ketons or ethers compounds as a solvent, dropwise adding dimethyl sulfate, carrying out the alkylation reaction for 0.5 to 10 hours at the temperature of 10 to 60 DEG C, controlling the PH value of the reaction solution between 7 and 8 by an alkalescent organic solvent during the alkylation reaction, and adding water for separate out crystals after the alkylation reaction, wherein the crystals are the compound shown as the formula I. In the preparation method, a one-step method is adopted to prepare the taxanes compound cabazitaxel shown as the formula I. The preparation method has the advantages of few reaction steps, mild reaction condition, short reaction time and high reaction efficiency, and is favorable for industrial production. Meanwhile, through controlling the dropping speed of an alkylating agent and the PH value of the reaction solution, the docetaxel can be prevented from decomposing and the purity of the reaction product can be enhanced.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of taxane compounds. Background technique [0002] Cabazitaxel (Jevtana), belonging to the taxane class, is a "gonadotropin-releasing hormone (GnRH)" receptor inhibitor drug developed by Sanofi-Aventis Pharmaceuticals of France, mainly for patients with advanced prostate cancer, and is a metastatic The first and only therapy to provide a significant survival benefit in the second-line treatment of sex hormone-refractory prostate cancer. On June 17, 2010, the US Food and Drug Administration (FDA) approved the combination of cabazitaxel (Jevtana) and prednisone (Prednisone) in the treatment of advanced prostate cancer. It is clinically recommended that docetaxel, a commonly used advanced prostate cancer drug, is ineffective The drug of choice for advanced, hormone-resistant prostate cancer, even in advanced disease. [0003] Cabazitaxel, with the molecular ...

Claims

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Application Information

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IPC IPC(8): C07D305/14
Inventor 李诚李靖姚全兴
Owner 重庆兴泰濠制药有限公司
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