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Synthetic method applicable to industrial production of Abiraterone acetate

A technology of abiraterone acetate and a synthetic method, applied in the synthetic field of industrialized mass production of abiraterone acetate, can solve the problem that the interval time between trifluoromethanesulfonic anhydride and alkali is short, cannot meet needs, and by-products 1 and 2 are removed, etc. question

Inactive Publication Date: 2012-07-11
深圳万乐药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The scale of 10-20g cannot meet the needs for industrial scale-up production
And this method requires adding trifluoromethanesulfonic anhydride and the interval time of alkali is very short, requires to add alkali slowly and control the time of adding alkali, is unfavorable for the preparation and operation on industrial production
[0013] The main technical problem of synthesizing abiraterone acetate is that by-product 1 is easily produced during the first step of synthesizing trifluoromethanesulfonate, and then generates by-product 2 by condensation reaction, and by-product 1 and 2 cannot be removed by recrystallization, and the The reaction raw materials cannot be completely converted into products, so it is necessary to control the reaction process conditions to reduce the generation of by-products in the first step of the reaction, improve the conversion rate, and simplify the purification process to adapt to industrial scale-up production

Method used

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  • Synthetic method applicable to industrial production of Abiraterone acetate
  • Synthetic method applicable to industrial production of Abiraterone acetate
  • Synthetic method applicable to industrial production of Abiraterone acetate

Examples

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Embodiment 1

[0030] Step 1 Preparation of 3β-acetoxyandrost-5,16-dien-17-yl triflate

[0031] Add dehydroepiandrosterone acetate (40 g, 121 mmol) to the reactor, add CH 2 Cl 2 (800ml) was stirred and dissolved, and cooled to -5-5°C under positive pressure of argon. Quickly join Tf 2 O (22.4ml, 133mmol, 1.1eq), stirred and reacted at -5~5°C for 40 minutes, then quickly added 2,6-lutidine (14.4ml, 121mmol, 1eq) at -5~5°C , The resulting reaction solution was stirred and reacted at room temperature for 3 hours. The reaction was quenched by adding water (400ml), the layers were separated and washed with CH 2 Cl 2 (200ml) to extract the aqueous layer, and combine the organic layers. The organic solution was washed with 2N HCl (200ml). After separation, use 120g anhydrous MgSO 4 Dry for 7 min, filter through a filter lined with acid alumina, and wash with CH 2 Cl 2 The filter cake was washed, and the filtrate and washings were concentrated to obtain a reddish-brown oil. HPLC showed tha...

Embodiment 2

[0037] Step 1 Preparation of 3β-acetoxyandrost-5,16-dien-17-yl triflate

[0038] Add dehydroepiandrosterone acetate (200g, 0.606mol) in the reactor, replace with argon three times, add CH 2 Cl 2 (4000ml) was stirred and dissolved, and cooled to -20~-15°C under the positive pressure of argon. Quickly join Tf 2O (112ml, 0.666mol, 1.1 equivalent), stirred and reacted at -20~-15°C for 40 minutes, then at -20~-15°C, quickly added 2,6-lutidine (70ml, 0.6mol, 1 equivalent), the resulting reaction solution was stirred and reacted at room temperature for 2 hours. The reaction was quenched by adding water (2000ml), the layers were separated and washed with CH 2 Cl 2 (1000ml) to extract the aqueous layer, and combine the organic layers. The organic solution was washed with 2N HCl (1000ml). After separation, anhydrous MgSO 4 (600g) was dried for 7 minutes, filtered through a filter lined with acid alumina, and washed with CH 2 Cl 2 The filter cake was washed, and the filtrate an...

Embodiment 3

[0044] Step 1 Preparation of 3β-acetoxyandrost-5,16-dien-17-yl triflate

[0045] Add dehydroepiandrosterone acetate (100g, 0.303mol) in the reactor, replace with argon three times, add CH 2 Cl 2 (2000ml) was stirred and dissolved, and cooled to -10~-5°C under the positive pressure of argon. Quickly join Tf 2 O (56ml, 0.333mol, 1.1 equivalent), stirred and reacted at -10~-5°C for 40 minutes, then quickly added N,N-diisopropylethylamine (DIPEA) (54ml , 0.6mol, 1 equivalent), the resulting reaction solution was stirred and reacted at room temperature for 5 hours. The reaction was quenched by adding water (1000ml), the layers were separated and washed with CH 2 Cl 2 (500ml) extracted the aqueous layer, and combined the organic layers. The organic solution was washed with 2N HCl (500ml). After separation, anhydrous MgSO 4 (300g) was dried for 7 minutes, filtered through a filter covered with diatomaceous earth, and washed with CH 2 Cl 2 The filter cake was washed and the ...

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Abstract

The invention discloses a synthetic method applicable to industrial mass production of Abiraterone acetate. According to the method, Abiraterone acetate is prepared through the steps of acylation, condensation and purification; in the step of acylation, dehydroepiandrosterone acetate is used as a raw material, the solvent of dichloromethane is added to dissolve dehydroepiandrosterone acetate under stirring, trifluromethanesulfonic anhydride is added at low temperature, a reaction at low temperature is maintained, then an alkaline catalyst is added at low temperature, and a reaction at room temperature is carried out. The method provided in the invention enables reaction byproducts to be reduced, operation to be simplified and purity of an HPLC test product to be more than 97% and is applicable to industrial mass production.

Description

technical field [0001] The invention relates to a synthesis method of chemical raw materials, in particular to a synthesis method suitable for industrial mass production of abiraterone acetate. Background technique [0002] Abiraterone is an oral inhibitor of cytochrome oxidase P450 (CYP450) c17, which reduces androgen levels by inhibiting the key enzyme in androgen synthesis - CYP450c17, and has effects on androgen in the testis and other parts of the body Inhibition, for the treatment of advanced prostate cancer. Abiraterone acetate is the prodrug of Abiraterone, also known as Abiraterone-3-acetate, its structural formula is: [0003] [0004] The compound and its synthesis method were first disclosed in WO93 / 20097A. The synthesis route is to use dehydroepiandrosterone acetate as a raw material to prepare its trifluoromethanesulfonate, and then combine it with diethyl (3-pyridyl) borane A two-step reaction leads to this compound: [0005] [0006] The base catalys...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00
Inventor 钱建彬秦怀伟刘飞键陈轶之张广明范晓林
Owner 深圳万乐药业有限公司
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