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Method for industrially producing butoconazole nitrate intermediate

A technology for butconazole nitrate and intermediates, which is applied in the field of industrial production of butconazole nitrate intermediates, can solve the problems of high cost, complicated production process of butconazole nitrate, product yield and purity that cannot meet industrialized production, and the like. Easy to operate, suitable for large-scale industrial production, reasonable in raw materials and dosage

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 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

[0051] 1-(2-Chloro-4-(4-chlorophenyl)butyl)-1hydro-imidazole was prepared according to the following procedure:

[0052] (1) Take 3kg of 1-(2-hydroxy-4-(4-chlorophenyl)butyl)-1hydro-imidazole, fully dissolve it in 30kg of dichloromethane, and add it dropwise at a rate of 1.5ml / s at 20°C 3.5 kg of thionyl chloride, slowly heated up to 33°C, held for 1 hour, then refluxed at 60°C for 1 hour, slowly cooled to below 15°C to obtain a reaction solution;

[0053] (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 water at a rate of 1.0 to 1.5kg / L Add anhydrous sodium carbonate, filter with suction, discard the solid, concentrate the liquid at 55°C until no dichloromethane evaporates, and dry to obtain the obtained product.

[0054] After testing, the yield of the product in this example was 99.18%. The target product and impurity content were detected by...

Embodiment 2

[0056] Compared with Example 1, the difference is only that the step (1) is specifically:

[0057] (1) Take 2kg of 1-(2-hydroxy-4-(4-chlorophenyl)butyl)-1hydro-imidazole, fully dissolve it in 25kg of dichloromethane, and add 2kg of it dropwise at a rate of 1ml / s at 15°C For thionyl chloride, slowly raise the temperature to 30°C, keep it warm for 0.5 hours, then reflux at 55°C for 0.5 hours, and slowly cool to 10°C to obtain a reaction solution.

[0058] After testing, the yield of the product in this example was 97.32%. 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 98.93%, 1-(1-chloro-4-(4-chlorophenyl The content of )butane-2-yl)-1 hydrogen-imidazole is 0.57%, and the content of 1-(2-hydroxy-4-(4-chlorophenyl)butyl)-1 hydrogen-imidazole is 0.25%.

Embodiment 3

[0060] Compared with Example 1, the difference is only that the step (1) is specifically:

[0061] (1) Take 5 kg of 1-(2-hydroxy-4-(4-chlorophenyl) butyl)-1 hydrogen-imidazole, fully dissolve it in 35 kg of dichloromethane, and add 5 kg of it dropwise at a rate of 2 ml / s at 25°C Thionyl chloride was slowly heated to 35°C, kept for 1.5 hours, then refluxed at 65°C for 1.5 hours, and slowly cooled to 20°C to obtain a reaction solution.

[0062] After testing, the yield of the product of this example was 98.14%. 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 98.97%, 1-(1-chloro-4-(4-chlorophenyl )butane-2-yl)-1H-imidazole content was 0.58%, and 1-(2-hydroxy-4-(4-chlorophenyl)butyl)-1H-imidazole content was 0.22%.

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Abstract

The invention relates to a method for industrially producing a butoconazole nitrate intermediate 1-(2-chlorine-4-(4-chlorphenyl) butyl)-1hydrogen-imidazole. The method comprises steps as follows: (1), 2-5 parts of 1-(2-hydroxyl-4-(4-chlorphenyl) butyl)-1hydrogen-imidazole is taken and sufficiently dissolved in 20-40 parts of dichloromethane, 2-5 parts of thionyl chloride are slowly and dropwise added at the temperature of 15 DEG C-25 DEG C, the mixture is slowly heated to 25 DEG C-65 DEG C for a sufficient reaction and cooled, and a reaction liquid is obtained; (2), cold water and anhydrous sodium carbonate are sequentially and slowly added to the reaction liquid obtained in the step (1), suction filtration is performed, solids are abandoned, a liquid is concentrated and dried, 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 the 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 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 彭开锋张英帅文峰球李三新龚云李伏君
Owner ZHUZHOU QIANJIN PHARMA
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