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Preparation method for abiraterone acetate

A technology of abiraterone acetate and volume ratio, applied in the direction of steroids, organic chemistry, etc., can solve the problems of using too many solvents, too long reaction steps, increasing production steps and costs, etc., to achieve mild reaction conditions and low total cost Effect

Active Publication Date: 2014-08-06
WUHAN BIOCAUSE PHARMA DEV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The reaction steps are too long, too many solvents are used, and the production steps and costs are increased

Method used

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  • Preparation method for abiraterone acetate
  • Preparation method for abiraterone acetate
  • Preparation method for abiraterone acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] The preparation of embodiment 1 Abiraterone acetate

[0043] 1. In a dry 500mL reaction flask, add 10g (30.3mmol) dehydroepiandrosterone acetate and 100mL tetrahydrofuran; cool down to 0°C, then slowly add 5.6mL (33.3mmol) of trifluoromethanesulfonic anhydride dropwise, the dropwise Then continue to add 3.0mL (30.6mmol) of 2-picoline dropwise, keep the temperature not exceeding 5°C during the period, react at 0°C for 2 hours after the drop, warm up to room temperature after the reaction, stir at constant temperature for 3 hours, and go directly to the next step .

[0044] 2. Under the protection of nitrogen, cool the reaction solution in the previous step to -5°C, add 20mL of potassium carbonate aqueous solution (containing potassium carbonate 15.2g, 110mmol) to it, keep the temperature not higher than 5°C, and then add bistriphenylphosphine 97 mg (0.14 mmol) of palladium dichloride and 5.1 g (41.5 mmol) of 3-pyridineboronic acid were heated to reflux and reacted overn...

Embodiment 2

[0046] The preparation of embodiment 2 Abiraterone acetate

[0047] 1. In a dry 500mL reaction flask, add 10g (30.3mmol) dehydroepiandrosterone acetate and 100mL toluene, cool down to below -5°C, then slowly add 5.6mL (33.3mmol) of trifluoromethanesulfonic anhydride dropwise, Continue to drop the mixture of 2-picoline 1.5mL (15.3mmol) and quinoline 1.9mL (15.3mmol) after the dropwise addition, and stir at -5°C for 3 to 3.5h after the dropwise addition, the color of the reaction solution turns into Brown; after heating up to 10°C, stirring at constant temperature for 2-2.5h, the color of the reaction solution turns brown. After the reaction was over, add 150mL of water to the reaction flask to quench the reaction, stir for 10 minutes, and separate the organic layer; the aqueous phase was extracted with 50mL of toluene, and the organic phase was combined; the organic layer was washed once with 50mL of water, and then washed with saturated brine (50mL ×3) The organic layer was w...

Embodiment 3

[0051] Embodiment 3 abiraterone acetate scale-up production technology

[0052] 1. Add 20L toluene to the 100L reactor, then add 4kg (12.12mol) dehydroepiandrosterone acetate, and start stirring. When the temperature dropped below -5°C, 2240 mL (13.32 mol) of trifluoromethanesulfonic anhydride was added dropwise, and the color of the reaction solution turned light green. After the trifluoromethanesulfonic anhydride was added dropwise, the mixture was stirred at -5°C for 10-15 minutes. Start to drop 11.36L of 2-picoline and quinoline toluene solution (containing 2-picoline 600ml (6.12mol), quinoline 760ml (6.12mol), toluene 10L). After the dropwise addition, stir at -5°C for 3 to 3.5 hours, and the color of the reaction solution turns brown; then raise the temperature to 10°C, stir at a constant temperature for 2 to 2.5 hours, and the color of the reaction solution turns brown. After the reaction was over, add 60L of water to the reaction kettle to quench the reaction, stir f...

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Abstract

The invention discloses a preparation method for abiraterone acetate. The preparation method comprises the following steps: dehydroepiandrosterone acetate and trifluoromethanesulfonic anhydride are subjected to sulfonyl reaction at the presence of an organic base catalyst to obtain a compound expressed in the formula II shown in the Specification; the compound and 3-pyridine organoboron componud or 3-pyridine organosilicon compound react at the presence of triphenyl phosphine palladium dichloride catalyst to obtain crude product of abiraterone acetate; the crude product is recrystallized in a proton solvent or a non-proton solvent to obtain abiraterone acetate crystal; the crystal is put into a diffluent solvent again to heat for dissolution and then the dissolved crystal is dropwise added to a less diffluent solvent and stirred for crystallizing solids to obtain micro-powder abiraterone acetate; the diffluent solvent is a mixture of more than two of acetone, ethanol and water at will and the less diffluent solvent is water. According to the preparation method, the course is reasonable, the operation is simple and convenient, the product quality is good, the yield is high, no column flowing, salifying and refining are needed in the whole technology process, the requirement for industrial scale is met and abiraterone acetate with the approximate grain size of 10 Mu m is obtained simultaneously.

Description

technical field [0001] The invention relates to the production field of fine chemical or pharmaceutical chemical products, in particular to the synthesis, production and micropowder crystallization process of a new anticancer drug abiraterone acetate. Background technique [0002] The chemical name of Abiraterone Acetate (Abiraterone Acetate, CAS: 154229-18-2) is (3β)-17-(3-pyridyl)-androst-5,16-dien-3-ol acetate, structural formula for: [0003] [0004] Abiraterone acetate is a CYP17 inhibitor indicated for the treatment of metastatic castration-resistant prostate cancer in combination with prednisone. In men with prostate cancer, the male hormone testosterone stimulates the growth of prostate tumors. Drug or surgical treatment is used to decrease testosterone production or to block the effects of testosterone. [0005] According to publicly reported literature, there are two kinds of synthetic methods of abiraterone acetate at present. [0006] The first method (WO...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00
CPCC07J43/003C07J1/0011C07J31/006
Inventor 程志刚代旭勇王旭东李绍奎李立威何思雨成森
Owner WUHAN BIOCAUSE PHARMA DEV
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