Synthesis method of 17-(3-pyridyl)-androst-4, 16-diene-3beta-ol acetate

A technology of pyridyl and androster, which is applied in the field of synthesizing 17--androster-4, which can solve the problems of high price of diethyl-3-pyridine borane, low purity of abiraterone acetate, complicated operation of pyridine zinc reagent, etc. problems, to achieve the effects of easy large-scale production, short reaction steps, and low equipment requirements

Inactive Publication Date: 2016-06-08
重庆瑞泊莱医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the process of preparing active sulfonate in this route, the raw materials are always incompletely reacted, and H-NMR monitoring is required, and diethyl-3-pyridine borane is expensive, which is not conducive to industrial production
[0007] In Chinese patent CN201210078438.2, abiraterone acetate is prepared by using dehydroepiandrosterone acetate to form a hydrazone, iodine and pyridine zinc reagent. In this route, the preparation of pyridine zinc reagent is complicated and the reaction conditions are harsh. Ultra-low temperature (-78°C), anhydrous and oxygen-free
Not c

Method used

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  • Synthesis method of 17-(3-pyridyl)-androst-4, 16-diene-3beta-ol acetate
  • Synthesis method of 17-(3-pyridyl)-androst-4, 16-diene-3beta-ol acetate
  • Synthesis method of 17-(3-pyridyl)-androst-4, 16-diene-3beta-ol acetate

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Embodiment 1

[0036] Embodiment 1: compound B synthesis

[0037]

[0038] Dissolve 30g (0.091mol) of compound A in 300ml of isopropyl ether, cool down to 0°C, add 90.5g (0.100mol) of 3-bromopyridine Grignard reagent dropwise, raise the temperature to room temperature for 18h, and use The reaction was quenched with saturated ammonium chloride aqueous solution, and the isopropyl ether was distilled off under reduced pressure. After evaporation, the mixture was extracted three times with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. Remove dichloromethane by distillation under reduced pressure. After the distillation is complete, add 300ml of methanol to the residue, add 23.3g (0.091mol) of Burgess reagent under stirring, heat and reflux for 1h, and add 23.3g (0.091mol) of Burgess reagent , TLC monitors the completion of the reaction, cooling, quenching the reaction with ice water, separating the layers, extractin...

Embodiment 2

[0039] Embodiment 2: the synthesis of compound C

[0040]

[0041] Dissolve 20g (0.051mol) of compound B in 100ml of ethanol, add 4.08g (0.102mol) of sodium hydroxide in 10ml of aqueous solution to the system, react at room temperature for 2 hours, monitor the completion of the reaction by TLC, filter, and wash the filter cake with water until neutral, 50 °C and dried to obtain 17.1 g of compound C with a yield of 95.8%.

Embodiment 3

[0042] Embodiment 3: Compound C is refined

[0043]

[0044] Add 15g (0.042mol) of compound C to 60ml of isopropanol, heat to reflux, dissolve, cool down to 0°C, crystallize for 1h, filter, wash the filter cake with isopropanol, and dry at 50°C to obtain 12.3g of compound C, Yield 82%.

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Abstract

The invention discloses a synthesis method of 17-(3-pyridyl)-androst-4, 16-diene-3beta-ol acetate. The reaction route is shown as the following: preparing a Grignard reagent from isopropyl chloride and magnesium powder, and then conducting Grignard exchange with 3-bromopyridine to obtain a 3-bromopyridine Grignard reagent; in the presence of isopropyl ether as a solvent, adding dehydroepiandrosterone acetate to carry out condensation reaction, then adding a Burgess reagent to perform dehydration so as to obtain an Abiraterone acetate crude product; then carrying out hydrolysis to obtain 17-(3-pyridyl)-androst-4, 16-diene-3beta-ol and performing recrystallization; and then adding an acetylation reagent to carry out reaction so as to obtain the target compound. The method provided by the invention has the advantages of simple operation, cheap and easily available raw materials, mild reaction conditions, low equipment requirement and high total yield, synchronous recovery of the used solvent and the like, and is low in production cost and easy for large-scale production, thus having significant industrial application value.

Description

technical field [0001] The invention relates to nitrogen-containing steroidal compounds, in particular to a method for synthesizing 17-(3-pyridyl)-androst-4,16-dien-3β-alcohol acetate. Background technique [0002] Abiraterone acetate (Abiraterone acetate, the chemical name is 17-(3-pyridyl)-androst-4,16-dien-3β-ol acetate) is an orally effective androgen developed by the American centocoroftho company Biosynthesis inhibitor; in 2011, it was approved for marketing by the US Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA), with the trade 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. lives of cancer patients. Recently, the US Food and Drug Administration and the European Agency for Medicines Evaluation also approved the addition of abiraterone acetate, which can be used before chemotherapy in ...

Claims

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Application Information

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IPC IPC(8): C07J43/00
Inventor 冉勇陈琳钟齐昌
Owner 重庆瑞泊莱医药科技有限公司
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