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Preparation method of Abiraterone

A technology of abiraterone and androsterone, which is applied in the field of preparation of abiraterone, can solve the problems of long coupling reaction time, low yield, difficult purification, etc., and achieve the promotion of economic and technological development, economic and environmental protection, and mild conditions Effect

Active Publication Date: 2013-12-04
GANSU LANYAO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The research of Chinese Patent No. CN10144155 points out that because the basic catalyst 2,6-di-tert-butyl-4-methylpyridine (DTBMP) is used in the preparation process of triflate, the elimination reaction of acetyl group is easy to occur, so that The yield is reduced and it is difficult to purify, which affects the industrialization effect of the process
However, due to the longer coupling reaction time in this synthetic route, the higher energy consumption, and the high price of diethyl (3-pyridyl) borane, it hinders large-scale production.

Method used

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  • Preparation method of Abiraterone
  • Preparation method of Abiraterone
  • Preparation method of Abiraterone

Examples

Experimental program
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Effect test

Embodiment 1

[0036] Add dehydroepiandrosterone (II) (7.2g, 25mmol) and dichloromethane 100mL in the dry reaction bottle, add chloromethyl methyl ether (8.0g, 100mmol) and diisopropylethylamine ( 13.6 g, 105 mmol), the temperature was raised to reflux for 12 hours, and TLC detected the end of the reaction. After cooling, the reaction solution was poured into ice water, the organic phase was separated, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, and dried over anhydrous magnesium sulfate. Dichloromethane was recovered under reduced pressure, and the residue was recrystallized from n-hexane to obtain 6.95 g of 3β-methoxymethyl ether dehydroepiandrosterone (II), with a yield of 83.7%.

Embodiment 2

[0038] Add dehydroepiandrosterone (II) (2.88g, 10mmol) and 50mL of dichloromethane in the dry reaction flask, add chloromethyl methyl ether (2.0g, 25mmol) and Na-Y zeolite (0.72g , 25% w / w), the temperature was raised to reflux for 7 hours, and TLC detected that the reaction was complete. After cooling, the solid was removed by filtration, and the organic phase was washed successively with 10% sodium bicarbonate solution, water and brine, and dried over anhydrous sodium sulfate. Dichloromethane was recovered under reduced pressure, and the residue was recrystallized from n-hexane to obtain 3.0 g of 3β-methoxymethyl ether dehydroepiandrosterone (II), with a yield of 90.4%.

Embodiment 3

[0040]Under the protection of nitrogen, add 3-pyridylmagnesium bromide in 2-methyltetrahydrofuran solution (1.0M, 12mL, 12mmol) into the dry reaction flask, cool down to 0-5°C, add 3β-methoxymethyl ether dropwise Dehydroepiandrosterone (II) (3.2 g, 10 mmol) in 2-methyltetrahydrofuran (50 mL) was reacted at a temperature below 20° C. for 1 hour. Add 50 mL of toluene and cool down to 5°C. Add 25% hydrochloric acid, stir for 30 minutes, let stand, separate the organic phase, wash with water twice, and dry over anhydrous magnesium sulfate. Toluene was recovered under reduced pressure, and the residue was recrystallized from ethyl acetate and n-hexane to obtain 3.75 g of 17-(3-pyridine)-17-hydroxy-androst-5-ene-3β-methoxymethyl ether (III) , yield 91.2%.

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Abstract

The invention discloses a preparation method of Abiraterone. The preparation method includes the steps of allowing dehydroepiandrosterone to engage in etherification reaction with RX to generate 3beta-alkoxy dehydroepiandrosterone (II), namely intermediate (II); allowing the intermediate (II) to engage in Grignard reaction with 3-pyridine magnesium bromide to obtain 17-(3-pyridine)-17-hydroxy-androstane-5-ene-3beta-alkyl ether (III), namely intermediate (III); allowing the intermediate (III) to engage in elimination reaction with 17-position hydroxy to obtain 17-(3-pyridine)-androstane-5, 16-diene-3beta-alkyl ether (IV), namely intermediate (IV); allowing the intermediate (IV) to engage in deprotection reaction to obtain Abiraterone (I). The preparation method is simple in process; raw materials are easy to obtain; quality is controllable; the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis method design and preparation of raw materials and intermediates, and particularly relates to a preparation method of abiraterone. Background technique [0002] Abiraterone acetate is an orally effective androgen biosynthesis inhibitor developed by Centocor Ortho Corporation of the United States. In 2011, it was approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA), with the product name Zytiga. The drug is clinically used in combination with prednisone (Prednisone) to treat metastatic advanced prostate cancer that has developed resistance to traditional hormone therapy. patient's life. Recently, the US Food and Drug Administration and the European Medicines Evaluation Agency also approved the addition of abiraterone acetate indications, which can be used before chemotherapy in patients with castration-resistant advanced metastatic ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00
Inventor 许学农
Owner GANSU LANYAO PHARMA CO LTD
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