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A kind of method of industrialized production butoconazole nitrate

A technology of butoconazole nitrate and imidazole, which is applied in the field of compound synthesis technology, can solve the problems of high cost, effective control, and complicated post-processing steps, and achieve the effects of low impurity content, simple operation, and reasonable raw materials and dosage

Active Publication Date: 2018-03-20
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 lacks effective control of impurities, resulting in post-processing such as purification. The steps are complicated, the cost is high, and the product yield and purity cannot meet the needs of industrial production

Method used

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  • A kind of method of industrialized production butoconazole nitrate
  • A kind of method of industrialized production butoconazole nitrate
  • A kind of method of industrialized production butoconazole nitrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Follow the steps below to produce butoconazole nitrate:

[0063] (1) Get 6kg 1-(2-chloro-4-(4-chlorophenyl) butyl)-1 hydrogen-imidazole, 6kg 2,6-dichlorothiophenol, 4kg anhydrous potassium carbonate and 50kg acetone, Reflux reaction at 65°C for 5.5 hours, add 1 kg of anhydrous potassium carbonate, reflux reaction at 65°C for 7.5 hours, slowly cool with circulating water at 0-4°C, centrifuge at 2825r / min for 30min, discard the solid, keep The liquid is the filtrate; the filtrate is concentrated at 65°C until no acetone is evaporated to obtain a concentrate;

[0064] (2) Take the concentrate obtained in step (1), add an extract that is 8 times the weight of the concentrate, and the extract is composed of ether, acetone and water in a weight ratio of 2.5:2:1.5; stir at 15°C After 10 minutes, let stand, discard the aqueous phase, and set aside the organic phase;

[0065] (3) Under ice-bath and stirring condition, in step (2) gained organic phase, dropwise add concentrated...

Embodiment 2

[0068] Follow the steps below to produce butoconazole nitrate:

[0069] (1) with embodiment 1;

[0070] (2) Take the concentrate obtained in step (1), add an extract that is 6 times the weight of the concentrate, and the extract is composed of ether, acetone and water in a weight ratio of 2:1:1; stir at 10°C After 5 minutes, let it stand still, discard the aqueous phase, and set aside the organic phase;

[0071] (3) with embodiment 1.

[0072] After testing, the yield of the product of this example was 91.36%. The target product and impurity content were detected by HPLC and standard substances. After testing, the content of the target product 1-(4-(4-chlorophenyl)-2-((2,6-dichlorophenyl)thio)butyl)-1 hydrogen-imidazole mononitrate is 90.17% , the content of the impurity 1-(2-chloro-4-(4-((2,6-dichlorophenyl)thio)phenyl)butyl)-1hydro-imidazole mononitrate was 1.25%.

Embodiment 3

[0074] Follow the steps below to produce butoconazole nitrate:

[0075] (1) with embodiment 1;

[0076] (2) Take the concentrate obtained in step (1), add an extract that is 10 times the weight of the concentrate, and the extract is composed of ether, acetone and water in a weight ratio of 3:3:2; stir at 20°C After 15 minutes, let it stand still, discard the aqueous phase, and set aside the organic phase;

[0077] (3) with embodiment 1.

[0078] After testing, the yield of the product of this example was 92.17%. The target product and impurity content were detected by HPLC and standard substances. After testing, the content of the target product 1-(4-(4-chlorophenyl)-2-((2,6-dichlorophenyl)thio)butyl)-1 hydrogen-imidazole mononitrate was 91.36% , the content of the impurity 1-(2-chloro-4-(4-((2,6-dichlorophenyl)thio)phenyl)butyl)-1hydro-imidazole mononitrate was 1.08%.

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Abstract

The invention relates to a method for producing butoconazole nitrate. The method comprises the following steps: (1) taking 1-(2-chloro-4-(4-chlorphenyl)butyl)-1-hydro-imidazole, 2,6-dichlorothiophenol and anhydrous potassium carbonate as raw materials to undergo heating reflux in acetone, after full reaction, cooling and filtering the reactant and concentrating the filtrate, thus obtaining a concentrate; (2) taking the concentrate obtained in the step (1) and adding extract liquor which comprises diethyl ether and water in a weight ratio of (2-3) to (1-2); after full extraction, discarding a water phase and retaining an organic phase for later use; (3) dropwise adding concentrated nitric acid to the organic phase obtained in the step (2) and carrying out filtration after stopping generating a precipitate; discarding the filtrate and washing and drying a filter cake, thus obtaining butoconazole nitrate. In the method provided by the invention, the conditions and parameters in the synthetic process are comprehensively and preferentially selected, and the impurities which are likely to be introduced in the production process are effectively controlled, thus increasing the production efficiency and 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 compound synthesis process, in particular to a method for industrialized production of butoconazole nitrate. Background technique [0002] Butoconazole nitrate is a clinically used drug for the treatment of vulvovaginal candida. It 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] Keith A.M.Walker, Allen C.Braemer and others published the article in 1978 "1-[4-(4-Chlorophenyl)-2-(2,6-dichlorophenylthio)-n-butyl]-1H-imidaz ole nitrate, a newpotent antifungal agent", the synthesis method of butoconazole nitrate is disclosed; in recent years, scholars such as Zhang Haibo have also reported the synthesis method of this drug. [0006] The main synthetic route of butoconazole nitrate is as follows: [0007] [0008] However, most of the research on the d...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D233/60
CPCC07D233/60
Inventor 李三新彭开锋凌勇根文峰球龚云李伏君
Owner ZHUZHOU QIANJIN PHARMA
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