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A kind of preparation method of dutasteride impurity i

A dutasteride impurity and nitrogen impurity technology, applied in the field of medicine, can solve the problems of difficult removal of impurities, side reactions, and no public literature reports on the preparation method of impurity I, and achieve the effect of improving the purity

Active Publication Date: 2016-04-06
GUANGDONG ZHONGSHENG PHARMA
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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
[0005] There are 9 kinds of impurities in the quality standard of dutasteride in the European Pharmacopoeia EP8.0, and the impurity I is not sold in the domestic and foreign markets, and there is no public literature reporting the preparation method of the impurity I

Method used

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  • A kind of preparation method of dutasteride impurity i
  • A kind of preparation method of dutasteride impurity i
  • A kind of preparation method of dutasteride impurity i

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1 Dutasteride and compound II carry out the condition investigation of condensation reaction

[0039] The inventor used pyridine, 2,6-lutidine, pyrrole, N-methylmorpholine, DBU, etc. as acid-binding agents to prepare impurity I, and also investigated the reaction solvent. The results are shown in Table 1 . It can be seen from Table 1 that the acid-binding agent DBU screened by the present invention has remarkable selectivity, and the condensation reaction occurs on the secondary amine at the 4-position, which can realize the preparation of impurity I, but the impurity I obtained when toluene is used as the reaction solvent The purity is only about 60%, and the time of prolonging the reflux reaction is also difficult to greatly improve the purity of the impurity I crude product; and the purity of the impurity I crude product obtained when xylene is used as the reaction solvent is as high as more than 85%, and the purity can reach 97% after column chromatograph...

Embodiment 2

[0042] The refining of the compound III of embodiment 2 technical grade

[0043] 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

[0044] The preparation of embodiment 3 compound II

[0045] Into a 3L reaction flask, add 250g of the refined product of Compound III obtained in Example 2 and 2.5L of dichloromethane, stir, control the temperature at 15-25°C, add 125mL of thionyl chloride dropwise, stir for 0.5h after dropping, and then Under the conditions of temperature 35-40°C and P<-0.08Mpa, the solvent was distilled off under reduced pressure, 2L of toluene was added to make a slurry for 0.5h, and filtered to obtain 370.5g of compound II.

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Abstract

The invention belongs to the technical field of medicines and discloses a preparation method of a dutasteride impurity I. The preparation method of the dutasteride impurity I comprises the following steps: preparing a compound III refined product, carrying out acylating chlorination on the compound III refined product to generate a compound II, carrying out condensation reaction on the compound II and 2,5-bis (trifluoromethyl) phenylamine in the presence of pyridine as an acid binding agent to obtain a dutasteride crude product, carrying out selective condensation reaction on the compound II and the dutasteride crude product in the presence of an appropriate acid binding agent to obtain a dutasteride impurity I crude product, dissolving the dutasteride impurity I crude product by virtue of dichloromethane, and carrying out column chromatography on silica gel by adopting ethyl acetate-petroleum ether, so that the high-purity dutasteride impurity I is obtained.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of dutasteride impurity I. 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...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J73/00
CPCC07J73/005
Inventor 谭珍友金联明黄爱君邵广志贺忠玉程志伟叶琼仙
Owner GUANGDONG ZHONGSHENG PHARMA
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