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Epristeride intermediate, preparation method of Epristeride intermediate, and preparation method of Epristeride

A technology of Epilite and intermediates, applied in steroids, organic chemistry, etc., can solve the problems of harsh preparation conditions and difficult reagents, and achieve the effect of avoiding column chromatography separation, less side reactions, and easy to obtain.

Inactive Publication Date: 2017-12-26
JIANGSU LIANHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The object of the present invention is to provide a kind of Apreglide intermediate and its preparation method, the preparation method of Apreglide, which aims to improve the existing harsh preparation conditions, the reagents used in the preparation process are not easy, etc.

Method used

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  • Epristeride intermediate, preparation method of Epristeride intermediate, and preparation method of Epristeride
  • Epristeride intermediate, preparation method of Epristeride intermediate, and preparation method of Epristeride
  • Epristeride intermediate, preparation method of Epristeride intermediate, and preparation method of Epristeride

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preparation example Construction

[0044] A preparation method of Apretide intermediate, which comprises the following steps: compound 3 is sulfonated with an alkaline reagent to generate compound 4; the reaction relational formula is as follows:

[0045]

[0046] Compound 3: N-tert-butyl-4-androsten-3-one-17-carboxamide;

[0047] In an embodiment of the present invention, the basic reagent is a non-nucleophilic base, such as: 1,8-diazabicycloundec-7-ene, lithium amide, lithium enolate and 2,6-bis At least one of tert-butyl-4-picoline. Further, the alkaline reagent is 1,8-diazabicycloundec-7-ene and 2,6-di-tert-butyl-4-methylpyridine. Preferably, the basic reagent is 2,6-di-tert-butyl-4-methylpyridine.

[0048] 1,8-Diazabicycloundec-7-ene; Molecular formula: C 9 h 16 N 2 , aka DBU.

[0049] 2,6-Di-tert-butyl-4-methylpyridine; Molecular formula: C 14 h 23 N, also known as DTBMP in English.

[0050] In this example, DTBMP was used as the alkaline reagent.

[0051] In this embodiment, the sulfonated p...

Embodiment 1

[0083] This embodiment provides a kind of Apretide intermediate, which is mainly prepared through the following steps:

[0084] Put compound 3 (3kg) and dichloromethane (24L) into the reaction kettle, drop the temperature to -10~0°C, add DBU (3.6kg), and add trifluoromethanesulfonic anhydride (6.8kg) dropwise at -10~0°C dichloromethane (6L) solution, add and keep warm for 2 hours. TLC tracking detection, when the raw material point disappeared, the reaction solution was quenched by adding 30 L of water, and the layers were separated. Evaporate under pressure to obtain 4.6 kg of dark red oil (Compound 4). The mass yield is 153%.

Embodiment 2

[0086] This embodiment provides a kind of Apretide intermediate, which is mainly prepared through the following steps:

[0087] Put compound 3 (3kg) and dichloromethane (24L) into the reaction kettle, cool down to -20~-10°C, add DBU (3.6kg), keep adding p-toluenesulfonic anhydride (8kg) at -20~-10°C Dichloromethane (6L) solution was added and incubated for 2 hours. TLC tracking detection, when the raw material point disappeared, the reaction solution was quenched by adding 30 L of water, and the layers were separated. Evaporate under pressure to obtain 5.8 kg of dark red oil (compound 4), with a mass yield of 193%.

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Abstract

The present invention relates to the field of medicaments, in particular to an intermediate of Aprelide, a preparation method thereof, and a preparation method of Aprelide. A preparation method of Aprelate intermediate, which comprises the following steps: compound 3 is reacted with basic reagent to generate compound 4 by sulfonation; compound 3 is reacted with basic reagent to generate compound 4; Chromatographic separation; the alkaline reagent used in the reaction process is easy to obtain, and the reaction conditions are mild. Moreover, the unit operation is reduced, the production cycle is shortened, and the production efficiency is improved. The production efficiency is high, and the economic benefits are improved.

Description

technical field [0001] The present invention relates to the field of medicaments, in particular to an intermediate of Aprelide, a preparation method thereof, and a preparation method of Aprelide. Background technique [0002] Epristeride, also known as elisteride, is a new type of anti-competitive 5α-reductase inhibitor, the chemical name is 17β-(N-tert-butyl-amino-formyl)androster-3, 5-diene-3-carboxylic acid. It is clinically used to treat benign prostatic hyperplasia (BPH). The mechanism of action of Apuletide: It can form a ternary complex with 5α-reductase and nicotinamide adenine dinucleotide phosphate (NADP+), thereby inhibiting the conversion of testosterone to DHT and making dihydrotestosterone (DHT) in the prostate The content is reduced to achieve the purpose of inhibiting benign prostatic hyperplasia. As a first-class new drug of our company, Apulet was approved for production by the State Drug Administration in September 2001 (approval certificate number: Guo...

Claims

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Application Information

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IPC IPC(8): C07J41/00
CPCC07J41/0066
Inventor 何秋秦雄剑褚青松俞波黄坤华庆松
Owner JIANGSU LIANHUAN PHARMA
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