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Methods for preparing abiraterone acetate and intermediate thereof

A technology of abiraterone acetate and asana, which is applied in a new preparation field of abiraterone acetate, a drug for treating prostate cancer, can solve the problems of limited purification effect, low yield of salt-forming purification operation, and low product quality

Active Publication Date: 2013-06-26
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this improved method still has some deficiencies: in the first step sulfonylation step, although the generation of by-product formula IV compound can be effectively controlled, still contain more raw material formula II compound in its prepared product formula III compound Conversion is complete (such as in a preferred embodiment, containing 25% unconverted formula II compound in the product formula III compound); in the second step condensation step, although the operation of column chromatography can be eliminated by salt-forming precipitation, the salt-forming The purification operation yield is not high, and the purification effect is limited (for example, in a preferred embodiment, the crude product of methanesulfonic acid and abiraterone acetate is salted, and its yield is only 64%, and the purity is only 87.7%), and after the salt is precipitated out, The mixture is thick and difficult to filter
[0018] Therefore, in order to develop a better abiraterone acetate preparation process, it is necessary to further improve the "four-step" preparation process to overcome the long reaction time existing in the prior art, the low product quality, and the need for Insufficient column chromatography operation, etc., making it more conducive to industrial production

Method used

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  • Methods for preparing abiraterone acetate and intermediate thereof
  • Methods for preparing abiraterone acetate and intermediate thereof
  • Methods for preparing abiraterone acetate and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Preparation of compound VIII:

[0102] Add 100g of dehydroepiandrosterone, 400ml of ethanol, and 40ml of 80% hydrazine hydrate into the reaction kettle, heat up to reflux reaction, after the reaction, cool the reaction solution, add 1L of water, first cool to room temperature and stir for 2 hours, then cool to 0~ 10°C, stirred for 1 hour, filtered, and the filter cake was dried under reduced pressure at about 60°C to obtain 103 g of the compound of formula VII; HPLC: 98.4%.

[0103] Add 1L of tetrahydrofuran to the reaction kettle, add 168g of iodine and 160ml of tetramethylguanidine, add dropwise a solution of 100g of the compound of formula VII and 2L of tetrahydrofuran at below 10°C, after the reaction is completed, filter, concentrate the filtrate under reduced pressure, and add di Chloromethane 2L and water 2L were added, then hydrochloric acid was added to adjust the pH to acidic, the organic layer was separated, washed with water and saturated sodium chloride sol...

Embodiment 2

[0105] Preparation of Compound IX:

[0106] Take 40g of compound VIII, dissolve in 1200ml of ethanol, add 15.5g of diethyl(3-pyridyl)borane, 720mg of bis(triphenylphosphine)palladium dichloride, add 53.6g of sodium carbonate and 240ml of water solution, heated to 70~75°C for 22 hours; cooled, filtered; half of the filtrate was concentrated under reduced pressure, and 1200ml of water was added to the remaining part to stir and crystallize, and filtered to obtain the crude compound IX; HPLC purity: 86.1%, which contained impurities X 0.9%.

[0107] The above crude product was mixed with 160ml of ethanol, stirred at about 65°C for 1 hour, cooled, and filtered; the filter cake was dried under reduced pressure at about 50°C to obtain 26g of compound IX; HPLC purity: 98.6%, which contained impurities X0.5% ; Yield: 74.1%.

[0108]

Embodiment 3

[0110] Preparation of Compound IX:

[0111] Take 10g of compound VIII, add 480ml of ethylene glycol dimethyl ether to dissolve, then add 4.8g of diethyl(3-pyridyl)borane, 360mg of bis(triphenylphosphine)palladium dichloride, 60ml of water, and then add carbonic acid Potassium 21g, heated to 75~80°C for 30 hours; cooled, filtered; half of the filtrate was concentrated under reduced pressure, and 500ml of water was added to the remaining part, stirred and crystallized, filtered to obtain the crude compound IX; HPLC purity: 80.5%, containing impurities X0.6%.

[0112] The above crude product was mixed with 40ml of methanol, stirred at about 55°C for 1 hour, cooled, and filtered; the filter cake was dried under reduced pressure at about 50°C to obtain 6g of compound IX; HPLC purity: 97.7%, containing impurity X0.5% ; Yield: 68.4%.

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Abstract

The invention relates to a method for preparing abiraterone which is a key intermediate of abiraterone acetate serving as a medicament for treating prostatic cancer and a method for preparing the abiraterone acetate by using the intermediate thereof. The methods are simple in processes, and the products have high purity and low content of impurities.

Description

[0001] technical field [0002] The invention relates to the fields of organic chemistry and pharmacy, in particular to a new preparation method of abiraterone acetate, a drug for treating prostate cancer. Background technique [0003] Abiraterone acetate, chemical name: (3β)-17-(3-pyridyl)-androst-5,16-dien-3-ol acetate, structure as shown in formula I. [0004] [0005] Abiraterone acetate can be converted into 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, so , Abiraterone not only inhibits the androgen produced by the testes but also other parts of the body such as the adrenal gland. Both the US FDA and the European EMEA approved abiraterone acetate for the treatment of advanced prostate cancer in 2011. [0006] Androgens can promote the growth of prostate cancer cells. At present, castration therapy, including drugs and surgery, is g...

Claims

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Application Information

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IPC IPC(8): C07J43/00
Inventor 邢乃果郑德平全继平石瑞娜邓杰罗杰叶文润
Owner CHONGQING PHARMA RES INST
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