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Method for preparing abiraterone acetate

A technology of abiraterone acetate and acetic acid, applied in the directions of steroids, organic chemistry, etc., can solve the problems of many by-products, long synthesis routes, and high cost of synthesis routes, and achieves few by-products, easy operation, and easy control of reaction conditions. Effect

Inactive Publication Date: 2012-12-12
SUN YAT SEN UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0012] In view of the high cost of the existing synthetic route using DHEA as raw material; the synthetic route using DHEA as raw material is relatively long, has many by-products, mass production requires column chromatographic separation and purification, and is in urgent need of development Corresponding alternative synthetic routes meet the requirements of convenient, economical and large-scale production of abiraterone acetate

Method used

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  • Method for preparing abiraterone acetate
  • Method for preparing abiraterone acetate
  • Method for preparing abiraterone acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 and Example 2 respectively provide the preferred preparation methods of intermediate (III) and intermediate (IV). It can also be prepared with reference to other methods in the art.

[0048] Example 1 intermediate (Ⅲ)

[0049] Dehydroepiandrosterone (II) acetate (4.0 g, 12.1 mmol) and 60 mL of ethanol were placed in a 200 mL round bottom flask, then hydrazine hydrate (80%, 2.9 mL, 48.4 mmol) and hydrazine sulfate (15.6 mg, 0.12 mmol), the reaction was stirred at room temperature for 3 days. The raw materials were completely reacted, and then 100 mL of ice water was added, and a white solid was precipitated, filtered with suction, and the filter cake was washed with ice water (2×30 mL), Et 2 O (2×30 mL) was washed, and the product was dried in vacuo to finally obtain 3.54 g of intermediate (Ⅲ), with a yield of 84.8%. 1 H NMR (400 MHz, CDCl 3 ): δ 5.39 (d, J = 5.2 Hz, 1H), 4.75 (s, 2H), 4.60 (ddd, J = 10.4, 8.5, 4.2 Hz, 1H), 2.35-2.26 (m, 3H), 2.17 (dt,...

Embodiment 2

[0050] Example 2 intermediate (Ⅲ)

[0051] Dehydroepiandrosterone (II) acetate (40 g, 121 mmol) and 600 mL of ethanol were placed in a 1000 mL round bottom flask, then hydrazine hydrate (80%, 29 mL, 484 mmol) and hydrazine sulfate (156 mg, 1.2 mmol), stirred at room temperature for 3 days. The raw materials were completely reacted, and then 600 mL of ice water was added, and a white solid was precipitated, filtered with suction, and the filter cake was washed with ice water (2×300 mL), Et 2 O (2×300 mL) was washed, and the product was dried in vacuo to finally obtain 35.9 g of intermediate (Ⅲ), with a yield of 86.0%.

Embodiment 3

[0052] Example 3 Intermediate (Ⅳ)

[0053] I 2 (3.1 g, 12.2 mmol) dissolved in 100 mL THF and 48 mL Et 2 In the mixed solution of O, under nitrogen protection at 0°C, 1,1,3,3-tetramethylguanidine (1.8 mL, 14.6 mmol) was added, and after 5 min, the intermediate (Ⅲ) (2.0 g, 5.8 mmol dissolved in 48 mL THF), the drop was completed within 1 h, and the stirring reaction was continued for 1 h. The raw materials were completely reacted, filtered with suction, and the filtrate was spin-dried, then placed in an oil bath at 80°C and heated for 4 hours with stirring, cooled, and added 60 mL of Et 2 O, suction filtered, and the filtrate was washed with HCl (1M, 3×50 mL), anhydrous Na 2 SO 4 After drying, removing the solvent and recrystallizing (ethanol: water = 5: 1), finally 2.4 g of intermediate (Ⅳ) was obtained, with a yield of 94.2%. 1 H NMR (400 MHz, CDCl 3 ): δ 6.14 (dd, J = 3.1, 1.6 Hz, 1H), 5.38 (d, J = 5.2 Hz, 1H), 4.60 (ddd, J = 10.3, 8.4, 4.4 Hz, 1H), 2.39-2.30 (...

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Abstract

The invention discloses a convenient, rapid and economical method for massively preparing abiraterone acetate. According to the method, dehydroepiandrosterone acetate is used as a starting material, a keto carbonyl group is converted to hydrazone, and the abiraterone acetate is directly synthesized through iodination and Suzuki coupling reaction. According to the method, the operation is simple and convenient, the total yield of the three-step reaction is 34.7%, the product purity is 98.5%, the column chromatography separation purification is not required in the postprocessing, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of abiraterone acetate. Background technique [0002] Abiraterone acetate, chemical name: (3β)-17-(3-pyridyl)-androst-5,16-dien-3-ol acetate, the structure is shown in (I). [0003] [0004] Abiraterone acetate is converted to abiraterone in the body. Abiraterone is a cytochrome oxidase P450 (CYP450) c17 inhibitor, which reduces androgen levels by inhibiting the key enzyme in androgen synthesis - CYP450c17. Androgens produced by the adrenal glands have inhibitory effects. [0005] The U.S. FDA approved abiraterone acetate for the treatment of advanced prostate cancer in April 2011. The treatment method of abiraterone acetate belongs to endocrine therapy, which can simultaneously inhibit the androgen produced in the testis and other parts of the body. Compared with the current conventional treatment method, it has better curative effect and low...

Claims

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Application Information

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IPC IPC(8): C07J43/00
Inventor 鲁桂严辉陈晖旋汤毅张霖泽
Owner SUN YAT SEN UNIV
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