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Abiraterone acetate preparation method

A technology of abiraterone acetate and palladium acetate, applied in directions such as steroids and organic chemistry, can solve problems such as limiting industrial application, and achieve the effects of large application value, simple production method and low cost

Active Publication Date: 2020-02-14
AURISCO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

3-pyridylzinc bromide can be obtained by reacting 3-bromopyridine with n-butyllithium and zinc bromide, which is relatively low in cost, but the reaction uses flammable and explosive butyllithium reagents, and requires low temperature to It can only be carried out at -78°C, which limits industrial applications

Method used

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  • Abiraterone acetate preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026]

[0027] Add 63.2g (0.40mol, 1.0equiv) of raw material 3-bromopyridine into a 1000mL three-neck flask equipped with magnetic stirring and reflux condenser, add 500mL of dry tetrahydrofuran as a solvent, replace with nitrogen and cool to 0°C, slowly drop Add 352mL of isopropylmagnesium bromide lithium chloride solution (1.25M, 0.44mol, 1.1equiv) and drop it over one hour. After the dropwise addition was completed, the temperature was raised to 25° C. for 3 hours, and 123 g (0.46 mol, 1.15 equiv) of solid zinc pivalate was added. After the addition was completed, the reaction was continued for 30 minutes, concentrated under reduced pressure to dryness, and vacuum-dried for two hours ( Be careful not to have air entering the reaction flask), to obtain solid 3-pyridine zinc pivalate and salt mixture 279g (0.30 ~ 0.34mol, conversion rate 75% ~ 85%), the solid is directly used in the next step without separation , all feeds are calculated based on the content of 279 grams ...

Embodiment 2

[0031]

[0032]Add 39.8 g (0.10 mol, 1.0 equiv) of the reaction compound 17-iodandrost-5,16-diene-3β-hydroxyl, 3-pyridine neopentyl Zinc acid 93.0g (0.10mol, 1.0equiv), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridine)palladium dichloride (PEPPSI-IPr) 0.68g (0.001mol, 0.01equiv), add 500mL tetrahydrofuran as a solvent, replace with nitrogen and heat to 50°C for 3 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure (distillation temperature was 40°C, vacuum degree was -0.08MPa), and a solution of 500 mL of dichloromethane and 11.1 g (0.11 mol, 1.1 equiv) of triethylamine was added, and 4-dimethylamino Pyridine 0.62g (0.005mol, 0.05equiv) was used as a catalyst, the temperature was lowered to 0°C, and 15.3g (0.15mol, 1.5equiv) of acetic anhydride was slowly added dropwise. After the addition was completed, the reaction was continued for three hours after the temperature was raised to 25°C, and filtered. W...

Embodiment 3

[0034]

[0035] Add 39.8 g (0.10 mol, 1.0 equiv) of the reaction compound 17-iodandrost-5,16-diene-3β-hydroxyl, 3-pyridine neopentyl Zinc acid 111.6g (0.12mol, 1.2equiv), dichloroditriphenylphosphine palladium 3.5g (0.005mol, 0.05equiv), add ethanol 500mL as a solvent, replace with nitrogen and heat to 70°C for 3 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure (the distillation temperature was 50°C, and the vacuum degree was -0.08MPa), and a solution of 500 mL of dichloromethane and 11.1 g (0.11 mol, 1.1 equiv) of triethylamine was added, and 4-dimethylamino Pyridine 0.62g (0.005mol, 0.05equiv) was used as a catalyst, the temperature was lowered to 0°C, and 15.3g (0.15mol, 1.5equiv) of acetic anhydride was slowly added dropwise. After the addition was completed, the reaction was continued for three hours after the temperature was raised to 25°C, and filtered. Wash the organic layer with 500mL of water and 500mL of 1N s...

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Abstract

The invention provides an abiraterone acetate preparation method, which comprises: dissolving 17-iodoandrosta-5,16-dien-3 beta-hydroxyl and 3-pyridine zinc neopentanoate in an organic solvent, reacting at 50-80 DEG C for 3-12 h under the catalysis of a palladium catalyst, removing the solvent after the reaction is finished, and esterifying with acetic anhydride to obtain an abiraterone acetate product. According to the invention, the method overcomes the defects of expensive raw materials, high cost, harsh reaction conditions and the like in the prior art, is low in cost, mild in preparation conditions, simple and convenient in production method and suitable for industrial production, and has high application value.

Description

technical field [0001] The invention relates to medicine preparation, in particular to medicine preparation, in particular to a preparation method of abiraterone acetate. Background technique [0002] Prostate cancer is one of the most common malignant tumors in men. In recent years, the incidence of prostate cancer in China has been on the rise, and most of them are in the middle and late stages when they are discovered. Studies have shown that androgens play an important role in the development of prostate cancer. At present, first-line endocrine therapy is the standard treatment mode for newly diagnosed advanced prostate cancer. This treatment method is effective for most patients in the initial stage, but after a median treatment time of 14 to 30 months, almost all patients have lesions All of them will gradually develop into castration-resistant prostate cancer (CRPC), with a median survival time of 1 to 2 years. Docetaxel has been approved for the first-line chemothe...

Claims

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Application Information

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IPC IPC(8): C07J43/00
CPCC07J43/003
Inventor 谢晓强尉海锋张德法张毅
Owner AURISCO PHARMACEUTICAL CO LTD
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