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A kind of method of industrialized production butoconazole nitrate

A technology for butconazole nitrate and imidazole, applied in the field of compound synthesis technology, can solve problems such as product yield and purity that cannot meet industrialized production, complicated post-processing steps, effective control and the like

Active Publication Date: 2018-05-01
ZHUZHOU QIANJIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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

[0066] Follow the steps below to produce butoconazole nitrate:

[0067] (1) Take 5kg 1-(2-chloro-4-(4-chlorophenyl)butyl)-1hydro-imidazole, 5kg 2,6-dichlorothiophenol, 2.5kg anhydrous potassium carbonate and 40kg acetone , reflux at 60°C for 5 hours, add 0.8kg of anhydrous potassium carbonate, reflux at 60°C for 7 hours, cool slowly with circulating water at 0-4°C, centrifuge at 2825r / min for 20min, discard the solid , retain the liquid, which is the filtrate; concentrate the filtrate at 60°C until no acetone is evaporated to obtain a concentrate;

[0068] (2) Take the concentrate obtained in step (1), add an extract composed of diethyl ether and water with a weight ratio of 2.5:1.5, after sufficient extraction, discard the aqueous phase, and leave the organic phase for subsequent use;

[0069] (3) Under ice-bath and stirring condition, in step (2) gained organic phase, dropwise add concentrated nitric acid, filter after stopping to generate precipitation; Discard filtrate, u...

Embodiment 2

[0072] Follow the steps below to produce butoconazole nitrate:

[0073] (1) Take 4kg 1-(2-chloro-4-(4-chlorophenyl) butyl)-1 hydrogen-imidazole, 4kg 2,6-dichlorothiophenol, 1kg anhydrous potassium carbonate and 30kg acetone, Reflux reaction at 55°C for 4.5h, add 0.5kg of anhydrous potassium carbonate, reflux reaction at 55°C for 6.5 hours, slowly cool with circulating water at 0-4°C, centrifuge at 2825r / min for 10min, discard the solid, The retained liquid is the filtrate; the filtrate is concentrated at 55°C until no acetone is evaporated to obtain the concentrate;

[0074] Steps (2), (3) are the same as in Example 1.

[0075] After testing, the yield of the product in this example was 89.58%. 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 91.44% , the content of the impurity 1-(2-chloro-4-(4...

Embodiment 3

[0077] Follow the steps below to produce butoconazole nitrate:

[0078] (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;

[0079] Steps (2), (3) are the same as in Example 1.

[0080] After testing, the yield of the product in this example was 95.3%. 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 92.25% , the content of the impurity 1-(2-chloro-4-(4-((2,...

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Abstract

The invention relates to a method for industrially producing butoconazole nitrate. The method comprises the following steps: (1) taking 1-8 parts of 1-(2-chloro-4-(4-chlorphenyl)butyl)-1-hydro-imidazole, 1-8 parts of 2,6-dichlorothiophenol, 1-5 parts of anhydrous potassium carbonate and 30-50 parts of acetone to undergo heating reflux reaction for 4-6 hours, then replenishing 0.1-1 part of anhydrous potassium carbonate, continuously carrying out heating reflux reaction for 5-9 hours, cooling and filtering the reactant and concentrating the filtrate, thus obtaining a concentrate; (2) taking the concentrate obtained in the step (1), adding extract liquor formed by an organic solvent and water, and after full extraction, 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 彭开锋文峰球白璐李三新龚云李伏君
Owner ZHUZHOU QIANJIN PHARMA
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