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Method for preparing abiraterone acetate

A technology of abiraterone acetate and abiraterone, applied in the direction of steroids, organic chemistry, etc., can solve the problems of failure to show large-scale production, yield and conversion rate need to be further improved, poor performance in yield, etc. question

Active Publication Date: 2020-06-30
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This application provides a kind of alternative method for abiraterone acetate, but the yield and the conversion rate of this technique need to be further improved
[0015] Several methods have been proposed for the preparation of 16,17-ene-17-(3-pyridyl) steroid derivatives, however, because the prior art is more or less poor in yield, the process conditions are harsh or the process introduction is difficult These methods have not been shown to be suitable for large-scale production, such as specific by-products removed by traditional techniques

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

[0104]

[0105] Add dehydroepiandrosterone (1) (150.00 g, 0.52 mol) and pyridine (750.00 g) sequentially into a 1000 mL three-necked flask, and stir to dissolve. Under the ice bath, control the temperature at 10-25°C, add benzoyl chloride (109.66g, 0.78mol) dropwise, remove the ice bath after dropping, stir until the reaction is complete, add water to quench the reaction, filter, filter the cake with water (150mL x 2 ), rinsed with air, and air-dried at 50° C. to obtain compound (2) as a white solid. The yield was 200.01 g, the yield was 98.0%, and the purity: 100% (HPLC).

[0106]

[0107] Compound (2) (100.00 g, 0.255 mol) and dichloromethane (2000 mL) were sequentially added into a 3000 mL three-neck flask, and cooled in an ice-water bath to obtain a white suspension. Under the protection of nitrogen, the temperature is controlled at -5 ~ 5°C, and trifluoromethanesulfonic anhydride (100.62g, 0.357mol) and triethylamine (28.36g, 0.280mol) are added dropwise in sequenc...

Embodiment 2

[0109] Embodiment 2: optimization of benzene methyl sulfonation conditions

[0110]

[0111] With reference to the operating process in Example 1 step 1, factors such as the types of benzoyl chloride consumption, alkali and solvent are investigated respectively in the reaction to obtain optimal process conditions

[0112] Numbering Dosage of Benzoyl Chloride base solvent yield 1 1.5 equivalent Triethylamine / DMAP Dichloromethane 74.9％ 2 1.5 equivalent pyridine NA 97.7％

Embodiment 3

[0114]

[0115] With reference to the operation process in step 2 of Example 1, factors such as the types of alkali and solvent in the reaction are investigated respectively to obtain optimal process conditions

[0116] Numbering Dosage of trifluoromethanesulfonic anhydride base temperature reflex yield 1 1.5 equivalent NMM -15～5℃ 92.8％ 2 1.5 equivalent pyridine -15～5℃ 93.0％ 3 1.5 equivalent Ac 2 O / AcOH / K 2 CO 3

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Abstract

The invention provides a method for preparing abiraterone acetate. Specifically, the invention relates to an improved method for synthesizing abiraterone or a derivative thereof through a key 3 beta-benzoyloxy intermediate. According to the process, intermediate DHEA 3-benzoyloxy ester is a solid, the intermediate with higher purity can be obtained through a crystallization method, and the processoperability is high. Meanwhile, benzoyl is strong in electric negative force, easy to react with hydroxyl and high in acylation rate, and a six-membered ring structure is twisted in a space structureof a benzoyl functional group, so that elimination reaction is not easy to perform, and generation of process byproducts is effectively avoided.

Description

technical field [0001] The invention relates to a method for preparing abiraterone acetate, in particular to an improved method for synthesizing abiraterone or its derivatives through a key 3β-benzoyloxy intermediate. Background technique [0002] Abiraterone acetate, a prodrug of abiraterone, is rapidly converted in vivo to abiraterone, a selective, irreversible steroidal inhibitor of CYP17 (17α-hydroxylase and C17,20-lyase) , which prevents testosterone synthesis in the testis, adrenal gland, and tumors by inhibiting enzyme activity, is used in combination with prednisone or prednisolone for the treatment of castration-resistant metastatic disease in patients who have failed androgen castration therapy and docetaxel chemotherapy Treatment of prostate cancer (mCRPC). [0003] According to literature reports, the general situation of Abiraterone acetate preparation process is the following: [0004] WO93 / 20097 reports the synthesis of compound (b) using acetyl dehydroepian...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00
CPCC07J43/003Y02P20/55
Inventor 李燕兵张辉薛州洋戴长春张甜甜万振江
Owner JIANGSU HENGRUI MEDICINE CO LTD
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