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Cabazitaxel intermediate as well as preparation method and application thereof

A cabazitaxel and intermediate technology, which is applied in the field of pharmaceutical synthesis, can solve the problems of harsh three-step synthesis reaction conditions, unsuitable for industrial production requirements, and low purity of the final product, and achieves simple preparation method, mild reaction conditions, and yield. high effect

Active Publication Date: 2013-12-04
SHANGHAI ACEBRIGHT PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The three-step synthesis reaction in this patent route has harsh conditions, poor selectivity, low yield, and low purity of the final product, and is not suitable for industrial production requirements.

Method used

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  • Cabazitaxel intermediate as well as preparation method and application thereof
  • Cabazitaxel intermediate as well as preparation method and application thereof
  • Cabazitaxel intermediate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment 1: preparation intermediate of the present invention

[0050]

[0051] Step A:

[0052] Under the protection of argon, 10.9 g (20 mmol, commercially available) of 10-deacetylbaccatin III (compound of formula 1) was dissolved in 100 mL of N-methylpyrrolidone (NMP); cooled to -30 ° C, and 1.68 g of sodium hydride was added (70mmol), insulated and stirred for 10 to 20 minutes; 11.36g (80mmol) of methyl iodide was added dropwise, and the insulated and stirred for 3 hours after dropping; naturally warming up to room temperature, stirring and reacting for 6 to 8 hours, TLC detection (developing agent is dichloromethane / Methanol=25 / 1, V / V) After the reaction of the raw materials is completed, the reaction solution is cooled to 0°C, and then 50mL of saturated ammonium chloride aqueous solution is added dropwise; Continue to stir for 1 hour, filter to obtain a light yellow solid; beat with 30% methanol aqueous solution; filter; vacuum-dry at 50°C for 8 hours; the...

Embodiment 2

[0059] Embodiment 2: preparation intermediate of the present invention

[0060] Step A:

[0061] Under argon protection, 10.9 g (20 mmol, commercially available) of 10-deacetylbaccatin III (compound of formula 1) was dissolved in 60 mL of N-ethylpyrrolidone (NEP) and 30 mL of tetrahydrofuran; cooled to -30 ° C, added tert Potassium butoxide 4.5g (40mmol), keep stirring for 10-20 minutes; add 4.24g (40mmol) of trimethyl orthoformate dropwise, keep stirring for 3 hours after dropping; naturally warm to room temperature, stir for 8-10 hours, TLC detection (The developer is dichloromethane / methanol=25 / 1, V / V) After the reaction of the raw materials is completed, the reaction solution is cooled to 0°C, and then 50mL of saturated ammonium chloride aqueous solution is added dropwise; Butyl ether, the solid slowly precipitated, and continued to stir for 1 hour after adding, and filtered to obtain a light yellow solid; slurred with 30% methanol aqueous solution; filtered; vacuum dried...

Embodiment 3

[0064] Embodiment 3: preparation intermediate of the present invention

[0065] Step A:

[0066] Dissolve 5.5g (10mmol) of 10-deacetylbaccatin III (compound of formula 1) in 60mL of pyridine and 40mL of toluene under the protection of argon; cool to -30°C, add 1.0g (41.7mmol) of sodium hydride, and keep stirring 10 to 20 minutes; add 3.8 g (40 mmol) of methyl bromide dropwise, and keep stirring for 3 hours after dropping; naturally warm up to room temperature, stir and react for 6 to 8 hours, and detect by TLC (developing agent is dichloromethane / methanol=25 / 1, V / V) After the reaction of the raw materials is completed, the reaction solution is cooled to 0° C., and then 50 mL of saturated ammonium chloride aqueous solution is added dropwise; after the drop is completed, 300 mL of isopropyl ether is added under stirring, and the solid is slowly precipitated out. After the addition, continue to stir for 1 hour, and filter. A small amount of toluene was rinsed to obtain a light ...

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Abstract

The invention discloses a cabazitaxel intermediate as well as a preparation method and an application thereof. The intermediate has a chemical structure formula shown as formula I shown in the description, and TES in the formula is the abbreviation of triethylsilane. The preparation method of the intermediate comprises a step B or a step A and the step B in the following synthetic route shown in the description, wherein the step A means that the compound of a formula 1 is subjected to a methylation reaction with a methylation agent for preparation of the compound of a formula 2; and the step B means that the compound of the formula 2 is subjected to a condensation reaction with the compound of a formula 3 for preparation of the intermediate I. The intermediate is subjected to hydrolysis under an acidic condition for removing the triethylsilane protective group, and thus cabazitaxel is prepared. According to the technical scheme, high-purity cabazitaxel can be synthesized by utilizing cheap and easily-available raw materials and with a low cost, large-scale industrialized production requirement on cabazitaxel is satisfied, and the preparation method is applicable to industrial application and has practical value.

Description

technical field [0001] The invention relates to a cabazitaxel intermediate 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. [0003] Cabazitaxel (trade name Jevtana) is a microtubule inhibitor developed by Sanofi-Aventis SA, which is used in combination with prednisone to treat steroid hormones previously treated with docetaxel-containing regimens. A new drug for patients with refractory metastatic prostate cancer, the specific chemical structure is as follows: [0004] [0005] Cabazitaxel is a paclitaxel analog with a very complex chemical structure and 11 chiral carbon atoms in the structure. It is similar in structure to the anticancer drugs paclitaxel and docetaxel. It is a white to off-white compound with the same mechanism of action ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18C07D305/14
CPCY02P20/55
Inventor 郭茂君余利兵杨勤刚任华森顾成龙
Owner SHANGHAI ACEBRIGHT PHARMA CO LTD
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