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Synthesis method of abiraterone acetate

A technology of abiraterone acetate and a synthetic method, applied in directions such as steroids, organic chemistry, etc., can solve problems such as long steps, reduce the generation of double bond by-products, low yield, etc., and achieve mild reaction conditions and production costs. Low cost, easy availability of raw materials

Inactive Publication Date: 2017-08-18
李建恒
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesis process steps are long, the yield is low, and in the Suzuki coupling process, due to the high activity of the iodide, it is easy to generate polymer impurities, which cannot be removed by recrystallization or column chromatography, and can only be purified by preparative chromatography. The pure product of biterone acetate cannot meet the needs of industrial production; (3) replace DTBMP with triethylamine in method (1), which reduces the generation of double bond by-products, and then removes the remaining raw materials in the reaction through recrystallization
This reaction increases the process steps, and the purity of the final product is only 96.4%, which cannot meet the quality standards of pharmaceuticals

Method used

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  • Synthesis method of abiraterone acetate

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Experimental program
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Effect test

Embodiment 1

[0021] A kind of synthetic method of abiraterone acetate, comprises the steps:

[0022] A. Add 0.95g (5mmol) p-toluenesulfonyl chloride and 15mL toluene to a 100ml round-bottomed flask in turn, stir and dissolve thoroughly to obtain solution X, slowly add the amount according to the substance at 15°C (solution X is cooled to 15°C) Add 1.5mL (10mmol) 80% hydrazine hydrate to solution X at a ratio of 1:2, drop it within 5 minutes; continue to react for 30 minutes, and a white precipitate appears in the flask. TLC analysis confirmed the reaction endpoint. After completion of the reaction, add 30ml of cold water at 10°C, stir, filter with suction, wash the filter cake 3-5 times with purified water, and dry to obtain 0.82g of white p-toluenesulfonyl hydrazide crystals, with a yield of 86.3% (document value: yield rate of 92%).

[0023] B, the synthesis of dehydroepiandrosterone-17-p-toluenesulfonylhydrazone

[0024] Add 0.75g (3mmol) dehydroepiandrosterone, 25mL methanol, and 0....

Embodiment 2

[0030] A. Add 1.02g (5.3mmol) p-toluenesulfonyl chloride and 15mL toluene to a 100ml round-bottomed flask in turn, stir and dissolve thoroughly to obtain solution X, slowly add 1.7mL (12mmol) 80% hydrazine hydrate dropwise to the solution at 15°C In X, the dripping was completed within 5 minutes; the reaction was continued for 30 minutes, and a white precipitate appeared in the flask. TLC analysis confirmed the reaction endpoint. After completion of the reaction, add 30ml of 10°C water to stir, filter with suction, wash the filter cake 3-5 times with purified water, and dry to obtain 0.93g of white p-toluenesulfonyl hydrazide crystals, with a yield of 86.7% (literature value: yield 92%).

[0031] B, the synthesis of dehydroepiandrosterone-17-p-toluenesulfonylhydrazone

[0032] Add 0.97g (3mmol) dehydroepiandrosterone, 25mL methanol, 1.08g p-toluenesulfonyl hydrazide to a 100ml round-bottomed flask in turn, stir well at room temperature to dissolve, add 0.1mL 0.2mol·L -1 Sul...

Embodiment 3

[0038] A. Add 1.08g (5.7mmol) p-toluenesulfonyl chloride and 15mL toluene to a 100ml round-bottomed flask in turn, stir and dissolve thoroughly to obtain solution X, slowly add 1.8mL (13mmol) 80% hydrazine hydrate dropwise to the solution at 15°C In X, the dripping was completed within 5 minutes; the reaction was continued for 30 minutes, and a white precipitate appeared in the flask. TLC analysis confirmed the reaction endpoint. After completion of the reaction, add 30ml of 10°C water to stir, filter with suction, wash the filter cake 3-5 times with purified water, and dry to obtain 0.94g of white p-toluenesulfonyl hydrazide crystals, with a yield of 85.6% (literature value: yield 92%).

[0039] B, the synthesis of dehydroepiandrosterone-17-p-toluenesulfonylhydrazone

[0040] Add 1.18g (3.3mmol) dehydroepiandrosterone, 25mL methanol, and 1.28g p-toluenesulfonyl hydrazide to a 100ml round-bottomed flask in turn, stir and dissolve at room temperature, add 0.1mL 0.2mol·L -1 S...

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Abstract

The invention discloses a synthesis method of abiraterone acetate. The method includes: taking dehydroepiandrosterone as the raw material, conducting condensation with p-toluenesulfonhydrazide, then carrying out coupling reaction with 3-bromopyridine, and conducting acetylation so as to synthesize the target product abiraterone acetate. According to the synthesis method provided by the invention, the route has mild reaction conditions, the raw materials are cheap and easily available, and the production cost is low.

Description

technical field [0001] The invention relates to a synthetic method of abiraterone acetate. Background technique [0002] The chemical name of Abiraterone acetate is (3β)-17-(3-pyridyl)-androst-5,16-diene-3-acetate, which is an oral CYP17 inhibitor developed by Centocor Ortho Corporation of the United States. On April 28, 2011, it was approved by the U.S. Food and Drug Administration (FDA) as a new anticancer drug, and it is used in combination with prednisone to treat castration-resistant prostate cancer. The trade name is Zyitga. Abiraterone acetate is an oral androgen synthesis inhibitor that inhibits 17α-hydroxylase / C17,20-lyase (CYP17). The results of clinical trials show that abiraterone acetate can significantly prolong the lives of patients with advanced prostate cancer, including those who have received one or two chemotherapeutic drugs containing docetaxel, but the condition still worsens, reducing the risk of death by 35%, and the side effects of the drug are ver...

Claims

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Application Information

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IPC IPC(8): C07J43/00
CPCC07J43/003
Inventor 李建恒马思跃
Owner 李建恒
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