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Method for industrially synthesizing butoconazole nitrate intermediate

A technology of butoconazole nitrate and intermediates, which is applied in the field of synthesis technology of butoconazole nitrate, can solve the problems that the product yield and purity cannot meet industrial production, the production process of butoconazole nitrate is complicated, and the cost is high

Active Publication Date: 2015-12-23
ZHUZHOU QIANJIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, most of the prior art studies on this drug are concentrated at the laboratory level. For the large-scale production of medicines, the production process of butoconazole nitrate provided by the prior art is complicated, the cost is high, and the product yield and purity are also low. Can not meet the needs of industrial production

Method used

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  • Method for industrially synthesizing butoconazole nitrate intermediate
  • Method for industrially synthesizing butoconazole nitrate intermediate
  • Method for industrially synthesizing butoconazole nitrate intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] 1-(2-Hydroxy-4-(4-chlorophenyl)butyl)-1hydro-imidazole was prepared as follows:

[0050] (1) Get 7kg concentration of 20% sodium hydride DMF solution, under ice bath condition, add dropwise 7kg concentration of 20% imidazole DMF solution while stirring at a speed of 2ml / s, and stir and react at 60°C for 60min; After cooling in an ice-salt bath, slowly add 5 kg of 1-chloro-4-(4-chlorophenyl)-2-butanol, stir and react at 60°C for 120 minutes, and cool in an ice-salt bath to obtain a reaction solution;

[0051] (2) Get the reaction solution gained in step (1), add 25% n-hexane accounting for the weight of the reaction solution, stir at a speed of 3 rpm for 15 min, then add ice water accounting for 350% of the weight of the reaction solution, Stir at a speed of 3 revolutions per second until the precipitation stops and then filter, wash the filter cake once with water accounting for 1 / 3 times the weight of the filter cake, and dry it by centrifugation at a speed of 2825 r / m...

Embodiment 2

[0054] Compared with Example 1, the difference is only that the step (2) is specifically:

[0055] (2) Get the reaction solution gained in step (1), add 20% n-hexane accounting for the weight of the reaction solution, stir at a speed of 1 rpm for 10 min, then add ice water accounting for 300% of the weight of the reaction solution, Stir at a speed of 1 revolution / second until the precipitation stops and then filter, wash the filter cake once with water accounting for 1 / 3 times the weight of the filter cake, centrifuge and dry at a speed of 2825r / min for 50min, Ethyl acetate and activated carbon with 2 times and 0.04 times the weight of the product obtained, stood at -7°C for 10 hours for recrystallization, and dried the recrystallized product at 45°C to obtain the product.

[0056] After testing, the yield of the product of this example was 69.31%. The target product and impurity content were detected by HPLC and standard substances. After testing, the content of the target ...

Embodiment 3

[0058] Compared with Example 1, the difference is only that the step (2) is specifically:

[0059] (2) Get the reaction solution gained in step (1), add 25% n-hexane accounting for the weight of the reaction solution, stir at a speed of 5 rpm for 20 min, then add ice water accounting for 400% of the weight of the reaction solution, Stir at a speed of 5 rpm until the precipitation stops and then filter, wash the filter cake twice with water accounting for 1 / 2 times the weight of the filter cake, and dry it by centrifugation at a speed of 2825r / min for 70 minutes Ethyl acetate and activated carbon 3 times and 0.06 times the weight of the product obtained, stood at -3°C for 16 hours for recrystallization, and dried the recrystallized product at 55°C to obtain the product.

[0060] After testing, the yield of the product of this example was 68.18%. The target product and impurity content were detected by HPLC and standard substances. After testing, the content of the target prod...

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Abstract

The invention relates to a method for industrially synthesizing a butoconazole nitrate intermediate. The method comprises steps as follows: (1), imidazole and sodium hydride are taken as raw materials, are heated and stirred in a DMF (dimethyl formamide) solution and are cooled after sufficient reaction, 1-chlorine-4-(4-chlorphenyl)-2-butanol is slowly dropwise added, the mixture is heated, stirred and cooled after sufficient reaction, and a reaction liquid is obtained; (2), n-hexane and ice water are sequentially added to the reaction liquid obtained in the step (1), sufficiently stirred and filtered after sediment separation stops, a filter cake is washed, centrifugally dried and recrystallized with ethyl acetate and activated carbon, and the butoconazole nitrate intermediate is obtained. According to the provided method, conditions and parameters in the synthesis process are comprehensively and preferentially selected, the purity and yield of products are improved, and the method is more suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a synthesis process of butoconazole nitrate, in particular to a method for synthesizing butoconazole nitrate intermediate 1-(2-hydroxyl-4-(4-chlorophenyl)butyl)-1 hydrogen-imidazole. Background technique [0002] Butoconazole nitrate (Butoconazole nitrate) is a clinically used drug for the treatment of vulvovaginal candida, which has the characteristics of significant curative effect, low recurrence rate, good tolerance, and low incidence of adverse reactions. [0003] The chemical structure of butoconazole nitrate is as follows: [0004] [0005] In the article "1-[4-(4-Chlorophenyl)-2-(2,6-dichlorophenylthio)-n-butyl]-1H-imidazolenitrate, anewpotentantifungalagent" published by KeithA.M.Walker and AllenC.Braemer in 1978, The synthesis method of butoconazole nitrate is disclosed; in recent years, scholars such as Zhang Haibo have also reported the synthesis method of the drug. [0006] The main synthetic route of butocona...

Claims

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Application Information

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IPC IPC(8): C07D233/60
CPCC07D233/60
Inventor 龚云张英帅彭开锋李伏君文峰球李三新
Owner ZHUZHOU QIANJIN PHARMA
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