A kind of preparation method of abiraterone acetate

A technology of abiraterone acetate and dilute sulfuric acid, applied in the direction of steroids, organic chemistry, etc., can solve the problems of high requirements for reaction vessels, long reaction time, expensive borane, etc., to avoid column chromatography separation and purification, suitable for industrialization The effect of shortening production and reaction time

Active Publication Date: 2016-04-13
SHANDONG NEWTIME PHARMA
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AI Technical Summary

Problems solved by technology

[0012] However, the formation of DHEA-17-hydrazone in this process requires additional catalysts hydrazine sulfate, 17-iodo-androst-5,16-dien-3β-ol and diethyl(3-pyridyl)boron The Suzuki coupling reaction of alkane needs to be refluxed in the presence of alkaline catalyst sodium carbonate. The reaction event is longer, consumes more energy, and has higher requirements on the reaction vessel, which brings a heavy burden to the treatment of three wastes. At the same time, the raw material diethyl ( 3-pyridyl) borane is very expensive, and the abiraterone acetate obtained by ethyl esterification requires column chromatographic separation, which is not suitable for large-scale production

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  • A kind of preparation method of abiraterone acetate
  • A kind of preparation method of abiraterone acetate
  • A kind of preparation method of abiraterone acetate

Examples

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Embodiment 1

[0026] The preparation of embodiment 1 dehydroepiandrosterone-17-hydrazone

[0027] Take a 1L three-necked flask, install a mechanical stirrer, add 28.8g (0.1mol) of dehydroepiandrosterone and 500mL ethanol, stir well at room temperature, then measure 20mL of 80% hydrazine hydrate and 2mL of 0.25mol / L dilute sulfuric acid, add it, and stir at room temperature for reaction 40 hours, TLC analysis, the reaction is complete, add 450mL water and stir for 30 minutes, then pour the reaction mixture into a beaker filled with 1L water, static crystallization for 2 hours, filter, wash the solid with 2 × 50mL water, and vacuum dry to obtain 29.8 g of white crystals (yield: 98.7%, mp: 204-205°C).

Embodiment 217

[0028] Preparation of Example 217-iodo-androst-5,16-diene-3β-alcohol

[0029] Take a 5L three-neck flask, add mechanical stirring, add iodine 110g (0.43mol), tetrahydrofuran 2L and diethyl ether 1.5L, nitrogen bubbles, stir well, cool down to 0°C, then add tetramethylguanidine 133mL (1.06mol), Dissolve 63.4 g (0.21 mol) of dehydroepiandrosterone-17-hydrazone in 1.6 L of tetrahydrofuran, then slowly add it dropwise to the reaction mixture, and maintain the reaction at 0 ° C for 3 hours. According to TLC analysis, the reaction is complete, and the reaction mixture is suction filtered. Concentrate the filtrate to dryness to obtain a brown oil, heat the oil to 100°C, stir and react under nitrogen atmosphere for 2.5 hours, cool to room temperature naturally, add 500 mL of ethyl acetate, stir and reflux for 30 minutes, cool, filter with suction, and adjust the pH of the filtrate with dilute hydrochloric acid To 4, the solution turns from brown to yellow, and the solution is washed w...

Embodiment 31

[0030] Preparation of Example 317-(3-pyridyl)androst-5,16-diene-3β-alcohol

[0031] (1) Take a 1L three-necked flask, install a mechanical stirrer, add 13.7mL (0.142mol) of 3-bromopyridine and 290mL of diethyl ether, respectively, blow nitrogen gas, cool down to -78°C, and slowly drop in the n-hexane solution of n-butyllithium ( 2M) 74.5mL, after the dropwise addition, continue stirring for 30 minutes, add 33.5g (0.149mol) of zinc bromide in ether solution 522mL, keep stirring and react for 1 hour, slowly rise to room temperature, concentrate under reduced pressure, blow nitrogen, add 600mLN, N -Dimethylformamide, fully stirred and dissolved, then added 17-iodo-androst-5,16-diene-3β-alcohol 39.8g (0.1mol) and tetrakistriphenylphosphinopalladium 116g (1mmol), room temperature Stir for 5 hours, adjust the pH of the reaction mixture to 1 with 1mol / L hydrochloric acid, then pour the reaction mixture into a beaker containing 500mL ethyl acetate and 500mL water, stir for 1h, separat...

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Abstract

The invention relates to a preparation method of abiraterone acetate. The method comprises: taking dehydroepiandrosterone as the raw material, which successively reacts with hydrazine hydrate and idoine so as to obtain 17-iodo-adrost-5, 16-diene-3beta-ol, which then undergoes a Negishi coupling reaction with 3-pyridine zinc halide to obtain abiraterone, and finally conducting esterification with acetyl chloride or acetic anhydride, thus obtaining the target product abiraterone acetate.

Description

technical field [0001] The invention relates to a preparation method of abiraterone acetate. Background technique [0002] The chemical name of Abiraterone acetate is 17-(3-pyridyl)androst-5,16-diene-3β-acetate, and its chemical structural formula is as follows: [0003] [0004] Abiraterone acetate is an oral androgen inhibitor that inhibits androgen synthesis by inhibiting the CYP450c17 enzyme. Abiraterone acetate can also provide a new effective treatment for prostate cancer patients whose tumors are still growing after drug treatment or surgical resection by reducing the level of tumor activity marker - "prostate-specific antigen (PSA)" . [0005] Abiraterone acetate was originally synthesized by British Technology Group Ltd., and then the company disclosed the structure and preparation method of the compound for the first time in WO93 / 20097, wherein the preparation method is to react dehydroepiandrosterone acetate with trifluoromethanesulfonic anhydride to form St...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J43/00
Inventor 赵志全王红波
Owner SHANDONG NEWTIME PHARMA
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