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Method for industrially producing butoconazole nitrate intermediate

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

Active Publication Date: 2015-12-30
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 research on the drug in the prior art is concentrated at the laboratory level. For the large-scale production of the drug, the production process of butoconazole nitrate provided by the prior art is complicated, the cost is high, and the product yield and purity cannot be achieved. Meet the needs of industrial production

Method used

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  • Method for industrially producing butoconazole nitrate intermediate
  • Method for industrially producing butoconazole nitrate intermediate
  • Method for industrially producing butoconazole nitrate intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] 1-(2-Chloro-4-(4-chlorophenyl)butyl)-1hydro-imidazole was prepared according to the following procedure:

[0054] (1) 5kg1-(2-hydroxy-4-(4-chlorophenyl)butyl)-1hydro-imidazole, fully dissolved in 35kg dichloromethane, drop 5kg at a rate of 1.5ml / s at 20°C For thionyl chloride, slowly heat up to 32°C, keep the temperature for 1 hour, then reflux at 60°C for 1 hour, and slowly cool to 15°C to obtain the reaction solution;

[0055] (2) Add water at 10°C at a rate of 0.5ml / s to the reaction solution obtained in step (1) while stirring, the volume ratio of the reaction solution to water is 0.005:1, and then add no Sodium carbonate water, filter with suction, discard the solid, concentrate the liquid at 55°C until no dichloromethane evaporates, and dry to obtain the obtained product.

[0056] After testing, the yield of the product in this example was 99.18%. The target product and impurity content were detected by HPLC and standard substances. After testing, the content o...

Embodiment 2

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

[0059] (2) Add water at 10°C at a rate of 0.1ml / s to the reaction solution obtained in step (1) while stirring, the volume ratio of the reaction solution to water is 0.004:1, and then add no Sodium carbonate water, filter with suction, discard the solid, concentrate the liquid at 50°C until no dichloromethane evaporates, and dry to obtain the obtained product.

[0060] After testing, the yield of the product in this example was 98.78%. The target product and impurity content were detected by HPLC and standard substances. After testing, the content of the target product 1-(2-chloro-4-(4-chlorophenyl)butyl)-1 hydrogen-imidazole is 98.86%, 1-(1-chloro-4-(4-chlorophenyl The content of )butane-2-yl)-1 hydrogen-imidazole was 0.66%, and the content of 1-(2-hydroxy-4-(4-chlorophenyl)butyl)-1 hydrogen-imidazole was 0.21%.

Embodiment 3

[0062] Compared with Example 1, the difference is only that the step (2) is specifically:

[0063] (2) Add water at 20°C at a rate of 1ml / s to the reaction solution obtained in step (1) while stirring, the volume ratio of the reaction solution to water is 0.006:1, and then add anhydrous Sodium carbonate, filter with suction, discard the solid, concentrate the liquid at 60°C until no dichloromethane evaporates, and dry to obtain the obtained product.

[0064] After testing, the yield of the product in this example was 98.65%. The target product and impurity content were detected by HPLC and standard substances. After testing, the content of the target product 1-(2-chloro-4-(4-chlorophenyl)butyl)-1 hydrogen-imidazole is 98.98%, 1-(1-chloro-4-(4-chlorophenyl The content of )butane-2-yl)-1 hydrogen-imidazole was 0.63%, and the content of 1-(2-hydroxy-4-(4-chlorophenyl)butyl)-1 hydrogen-imidazole was 0.23%.

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Abstract

The invention relates to a method for industrially producing a butoconazole nitrate intermediate 1-(2-chloro-4-(4-chlorphenyl)butyl)-1-hydro-imidazole. The method comprises the following steps: (1) taking 1-(2-hydroxy-4-(4-chlorphenyl)butyl)-1-hydro-imidazole and thionyl chloride as raw materials to undergo heating reflux in dichloromethane, and after full reaction, cooling the reactant, thus obtaining a reaction liquid; and (2) slowly adding cold water and anhydrous sodium carbonate to the reaction liquid obtained in the step (1) in sequence, carrying out suction filtration, discarding the solid, concentrating the liquid and drying the concentrate, thus obtaining the butoconazole nitrate intermediate. In the method provided by the invention, the conditions and parameters in the synthetic process are comprehensively and preferentially selected, thus increasing the purity and yield of the product. Therefore, the method is more suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a production process of butoconazole nitrate, in particular to a production method of butoconazole nitrate intermediate 1-(2-chloro-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 butoconazole...

Claims

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Application Information

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IPC IPC(8): C07D233/56
CPCC07D233/56
Inventor 李伏君白璐彭开锋文峰球李三新龚云
Owner ZHUZHOU QIANJIN PHARMA
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