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Method for industrial process production of butoconazole nitrate

A technology of butoconazole nitrate and imidazole, which is applied in the field of production technology of butoconazole nitrate, can solve the problems of complex post-processing steps, lack of impurities, and high cost

Active Publication Date: 2016-01-06
ZHUZHOU QIANJIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] 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 lack of continuity makes it difficult to meet the needs of industrial mass production

Method used

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  • Method for industrial process production of butoconazole nitrate
  • Method for industrial process production of butoconazole nitrate
  • Method for industrial process production of butoconazole nitrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Butoconazole nitrate is produced according to the following sequential steps:

[0054] (1) Get 2kg of magnesium powder, 50ml of ether and a catalytic amount of iodine, add 40kg of p-chlorobenzyl ether solution with a concentration of 0.27g / ml dropwise at a rate of 3ml / s at 35°C, and after the dripping, place the solution at 37°C React for 1 hour to obtain p-chlorobenzyl Grignard reagent; then slowly add 20 kg of epichlorohydrin ether solution with a concentration of 0.35 g / ml dropwise, and react at 37°C for 1.5 hours to obtain a reaction solution; 1. Under the condition of constant speed stirring, in the reaction solution, drip the sulfuric acid with a concentration of 25% at a speed of 2ml / s, and stop the dripping when there is no solid residue; leave standstill for 10 minutes after stirring at a constant speed for 10 minutes to make the liquid layer; discard the water phase, take the organic phase and concentrate it under the conditions of -0.01MPa and 55°C until no d...

Embodiment 2

[0061] Butoconazole nitrate is produced according to the following sequential steps:

[0062] (1) get 1.5kg magnesium powder, the iodine of the diethyl ether of initiation amount and catalytic amount, the mass volume ratio of described magnesium powder and initiation diethyl ether is 1.5kg / 50ml; Drop 35kg with the speed of 2ml / s at 30 ℃ Concentration of 0.25g / ml p-chlorobenzyl ethyl ether solution, react at 35°C for 0.5 hours after dropping to get p-chlorobenzyl Grignard reagent; then slowly add 15 parts of epoxy chloride with a concentration of 0.33g / ml Propane ether solution, react at 35 DEG C for 1 hour after dropping, to obtain the reaction liquid; in the described reaction liquid, drip the sulfuric acid with a concentration of 24% at a speed of 1 ml / s at 0 DEG C and uniform stirring condition, until no When the solid remains, stop the dropwise addition; stir at a constant speed for 5 minutes and then let stand for 8 minutes to separate the liquid; discard the water phase,...

Embodiment 3

[0070] Butoconazole nitrate is produced according to the following sequential steps:

[0071] (1) get 2.5kg magnesium powder, the iodine of the diethyl ether of initiation amount and catalytic amount, the mass volume ratio of described magnesium powder and initiation diethyl ether is 2.5kg / 50ml; Drop 45kg with the speed of 4ml / s at 40 ℃ Concentration of 0.25 ~ 0.3g / ml p-chlorobenzyl ethyl ether solution, react at 40°C for 1.5 hours after dropping to get p-chlorobenzyl Grignard reagent; then slowly add 25 kg of 0.33 ~ 0.37g / ml Epichlorohydrin ether solution, react at 40°C for 2 hours after dropping, to obtain a reaction solution; add sulfuric acid with a concentration of 26% to the reaction solution at a rate of 3ml / s at 10°C under constant stirring , stop dropping when there is no solid residue; stir at a constant speed for 15 minutes and let stand for 12 minutes to separate the liquid; discard the water phase, take the organic phase and concentrate it at 0MPa and 60°C until n...

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Abstract

The invention relates to a method for industrial process production of butoconazole nitrate. The method comprises the step that an intermediate product 1-chlorine-4-(4-chlorphenyl)-2-butanol, an intermediate product 1-(2-hydroxy-4-(4-chlorphenyl)butyl)-1 hydrogen-imidazole, an intermediate product 1-(2-chlorine-4-(4-chlorphenyl)butyl)-1 hydrogen-imidazole, a butoconazole nitrate crude product and a butoconazole nitrate finished product are sequentially synthesized. 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 the products are increased, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a production process of butoconazole nitrate, in particular to a method for industrialized continuous 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] However, most of the research on the drug in the prior art is concentrated at the...

Claims

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Application Information

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IPC IPC(8): C07D233/60
CPCC07D233/60
Inventor 李伏君彭开锋文峰球凌勇根李三新龚云
Owner ZHUZHOU QIANJIN PHARMA
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