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Preparation method of dutasteride impurity I

A technology of dutasteride impurity, aza, applied in the field of medicine, can solve the problems such as impurity being difficult to remove, no open literature report impurity I preparation method, unfavorable control, etc., to achieve the effect of improving the purity

Active Publication Date: 2015-01-21
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 EP 8.0, and the impurity I in it 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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  • Preparation method of dutasteride impurity I
  • Preparation method of dutasteride impurity I
  • Preparation method of dutasteride impurity I

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1 Investigation of the conditions for the condensation reaction of dutasteride and compound II

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

Embodiment 2

[0042] Example 2 Refinement of technical grade compound III

[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 times, and the solids are washed at 30-35°C. ℃ of blast drying for 24h to obtain 375.0g of compound III refined product, the yield is 75.0%, the purity is 99.99%, and the HPLC spectrum of its related substances is as follows figure 1 shown.

Embodiment 3

[0044] Example 3 Preparation of Compound II

[0045] In a 3L reaction flask, add 250g of compound III refined product prepared in Example 2 and 2.5L of dichloromethane, stir, control the temperature to 15-25°C, add 125mL of thionyl chloride dropwise, stir for 0.5h after dropping, and then put The solvent was evaporated under reduced pressure at a temperature of 35-40°C and P<-0.08Mpa, 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 field of medical technology, and specifically relates to a preparation method of dutasteride impurity I. Background technique [0002] Dutasteride is a second-generation 5a reductase inhibitor and is currently the only drug that inhibits both type I and type II 5a reductase. Dutasteride was developed by GlaxoSmithKline and was approved by the US FDA for the treatment of benign prostatic hyperplasia in November 2001. It was first launched in the US in January 2003. [0003] Chinese patent CN1473165B et al. discloses the preparation of dutasteride by chloriding 3-keto-4-aza-5α-androstane-1-en-17β-carboxylic acid with thionyl chloride and then performing a condensation reaction with the corresponding aniline. Methods. The starting material of this method, 3-keto-4-aza-5α-androstane-1-en-17β-carboxylic acid, has been commercially produced and has a wide range of sources. The reaction conditions of each step of this method are...

Claims

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Application Information

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Patent Type & Authority Applications(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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