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Method for industrial production of butoconazole nitrate

A technology for butconazole nitrate and imidazole, applied in the field of chemical synthesis technology, can solve the problems of lack of impurities, effective control, complicated post-processing steps, etc., and achieve the effects of easy purification and purification, reducing the generation of impurities, and improving the purity and yield.

Active Publication Date: 2016-01-06
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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  • Method for industrial production of butoconazole nitrate
  • Method for industrial production of butoconazole nitrate
  • Method for industrial production of butoconazole nitrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Follow the steps below to produce butoconazole nitrate:

[0068] (1) Take 6kg1-(2-chloro-4-(4-chlorophenyl)butyl)-1hydro-imidazole, 6kg2,6-dichlorothiophenol, 4kg anhydrous potassium carbonate and 50kg acetone, 65℃ Under reflux reaction for 5.5 hours, add 1kg 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, It is the filtrate; the filtrate is concentrated at 65°C until no acetone is evaporated to obtain a concentrate;

[0069] (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;

[0070] (3) under the stirring condition of ice bath, 1.5 rev / s, in step (2) gained organic phase, add th...

Embodiment 2

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

[0075] (1), (2) are with embodiment 1;

[0076] (3) under the stirring condition of ice bath, 1 rev / s, in step (2) gained organic phase, add the nitric acid that concentration is 69% with the speed of 1ml / s dropwise, to stop generating after precipitation at 2825r / min centrifuge for 20min under the condition of 2825r / min, discard the liquid and keep the solid; The retained solid was mixed with 6 times the weight of acetone, stirred thoroughly, centrifuged at a speed of 2825r / min for 20min, discarded the liquid, retained the solid, and dried at 45°C and -0.5Mpa for 3 hours to obtain the crude product of butoconazole nitrate ;

[0077] (4) with embodiment 1.

[0078] After testing, the yield of the product of this example was 87.33%. After testing, the content of the target product 1-(4-(4-chlorophenyl)-2-((2,6-dichlorophenyl)thio)butyl)-1 hydrogen-imidazole mononitrate is 99.59% , the content of impurity 1-(4...

Embodiment 3

[0080] Follow the steps below to produce butoconazole nitrate:

[0081] (1), (2) are with embodiment 1;

[0082] (3) under the stirring condition of ice bath, 2 turns / seconds, in step (2) gained organic phase, add the nitric acid that concentration is 69% with the speed of 3ml / s, to stop generating precipitation at 2825r / min after rotating speed Centrifuge for 40min under the condition of 2825r / min, discard the liquid and keep the solid; the filter cake is mixed with 4 times the weight of diethyl ether and then fully stirred. The retained solid was mixed with 8 times the weight of acetone, then fully stirred, centrifuged at a speed of 2825r / min for 40min, the liquid was discarded, the solid was retained, and dried at 55°C and 0.5Mpa for 7 hours to obtain the crude product of butoconazole nitrate;

[0083] (4) with embodiment 1.

[0084] After testing, the yield of the product in this example was 85.11%. After testing, the content of the target product 1-(4-(4-chlorophenyl)-...

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Abstract

The invention relates to a method for industrial production of butoconazole nitrate. The method comprises the following steps that firstly, 1-(2-chlorine-4-(4-chlorphenyl)butyl)-1 hydrogen-imidazole is mixed with 2,6-dichoribenzene thiophenol, anhydrous potassium carbonate and acetone, a heating reflux reaction is carried out, anhydrous potassium carbonate is supplemented, the heating reflux reaction is continued, cooling and filtering are carried out, and concentrate is obtained after filter liquor is concentrated; secondly, extract liquor containing diethyl ether and water is added in the concentrate, after sufficient extraction is carried out, a water phase is discarded, and an organic phase is reserved; thirdly, concentrated nitric acid is dripped into the obtained organic phase on ice bath and stirring conditions, and filtering is carried out when sediment stops being generated; the filter liquor is discarded, a filter cake is washed with diethyl ether and acetone in sequence, and the metric acid butoconazole is obtained after the filter cake is dried. According to the method, conditions and parameters in the synthesizing process are comprehensively optimized, impurities likely to be introduced in the production process are effectively controlled, the production efficiency is improved, the purity and yield of products are increased, and the method is more suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a chemical synthesis process, in particular to a method for industrialized production of butoconazole nitrate. 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 nitrate is as follows: [0007] [0008] However, most of the r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/60
CPCC07D233/60
Inventor 龚云凌勇根彭开锋文峰球李三新李伏君
Owner ZHUZHOU QIANJIN PHARMA
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