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Preparation method of dutasteride

A technology of dutasteride and androsteride, applied in the field of medicine, can solve the problems such as difficult removal of impurities, unfavorable control, side reactions, etc., achieves guaranteed yield, avoids the generation of dutasteride by-products, and mild reaction conditions Effect

Active Publication Date: 2014-12-24
GUANGDONG XIANQIANG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This refining method can reduce the content of the dihydro impurity in the starting material from 0.63% to below 0.1%, but because formic acid is very easy to combine with 3-keto-4-aza-5α-androstane-1- The 1-position ethylenic bond on the alkene-17β-carboxylic acid is added, so that a side reaction occurs. At the same time, after washing with methanol, due to the residue of methanol, the starting material will react with methanol after being chlorinated by thionyl chloride to produce dutasterone Aminomethylated impurity (3-keto-4-aza-5α-androstane-1-ene-17β-carboxylate methyl ester)
Therefore, use methanol to wash after refining with formic acid, and formic acid can effectively remove the dihydro impurity (4-aza -5α-androstane-3-one-17β-carboxylic acid) at the same time, the residue of methanol will lead to the occurrence of side reactions, and the impurities produced by the side reactions are difficult to remove in subsequent reactions, which is not conducive to dutasteride bulk drug Control of related substances in

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1 The investigation of compound III refining and washing solvent

[0038] The inventors used different solvents to refine and wash the industrial-grade compound III, and the results are shown in Table 1. As can be seen from Table 1, the use of formic acid to wash compound III with acetone after beating at room temperature can effectively remove the residual alcohol reagent in the starting material, making the residual alcohol reagent ≤ 0.1%, and also avoiding the compound III. The addition reaction of ethylenic bonds produces new impurities, which can effectively control the product quality of dutasteride.

[0039] Table 1 Effect of different refining and washing solvents on dutasteride

[0040] Preface

[0041] No

[0042] Remarks: The detection of related impurities is carried out in the raw material drug dutasteride after positioning with the EP system applicability reference substance.

Embodiment 2

[0043] Example 2 The purification of industrial-grade compound III

[0044] In a 3L reaction flask, add 500g of industrial grade compound III and 1.5L of anhydrous formic acid, stir and beat at 30-35°C for 5h, filter, and wash the filter cake with acetone, 0.5L each time, for a total of 2 washes, the solid is at 30-35 ℃ air-dried for 24 hours to obtain 375.0 g of the refined product of compound III, with a yield of 75.0% and a purity of 99.99%. The HPLC spectrum of its related substances is as follows: figure 1 shown.

Embodiment 3

[0045] Example 3 Refining of Industrial Grade Compound III

[0046] Into a 3L reaction flask, add 500g of industrial grade compound III and 1.2L of anhydrous formic acid, stir and beat at 30-35°C for 4 hours, filter, and wash the filter cake with acetone, 0.5L each time, for a total of 2 washes, the solid is at 30-35 ℃ blast drying for 20 h to obtain 373.6 g of compound III refined product.

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Abstract

The invention belongs to the technical field of medicine, and provides a preparation method of dutasteride. The preparation method comprises the following steps: A) an industrial-grade compound III is washed by acetone after beaten and refined by formic acid, and a refined compound III product is obtained; B) the refined compound III product has a chlorination reaction to generate a compound II; C) the compound II has a condensation reaction with 2,5-bis (trifluoromethyl) phenylamine, a product is cooled and filtered, a filtrate is collected, a hydrochloric acid solution is added for washing, an organic phase is separated, pressure is reduced to evaporate s solvent, and a crude dutasteride product is obtained; and D) the crude dutasteride product is dissolved by an organic solvent and decolorized, an anti-solvent is added for crystallization, and high-purity dutasteride is obtained. Side reactions are reduced, high-purity dutasteride can be obtained through preparation, and the productive cost is reduced.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of dutasteride. Background technique [0002] Dutasteride is a second-generation 5a reductase inhibitor, and currently the only drug that simultaneously inhibits type I and type II 5a reductase. Dutasteride was researched and developed by GlaxoSmithKline and was approved by the US FDA in November 2001 for the treatment of benign prostatic hyperplasia. It was first launched in the US in January 2003. [0003] Chinese patent CN1473165B etc. disclosed that 3-keto-4-aza-5α-androstane-1-ene-17β-carboxylic acid was chlorinated with thionyl chloride and then condensed with corresponding aniline to prepare dutasteride Methods. The starting material of the method, 3-keto-4-aza-5α-androstane-1-ene-17β-carboxylic acid, has been commercially produced and has a wide range of sources, and the reaction conditions of each step of the method are mild and suitab...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J73/00
Inventor 谭珍友金联明黄爱君邵广志贺忠玉程志伟杜静
Owner GUANGDONG XIANQIANG PHARMA
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