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Industrial production method for butoconazole nitrate intermediate

A technology of butoconazole nitrate and intermediates, which is applied in the field of production of butoconazole nitrate intermediate 1-chloro-4--2-butanol, can solve the problem that the product yield and purity cannot meet industrial production, butoconazole nitrate Solve the problems of complex azole production process and high cost, and achieve the effect of being suitable for large-scale industrial production, reasonable raw materials and dosage, and easy operation

Active Publication Date: 2016-03-09
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 is complicated, the cost is high, and the product yield and purity cannot be achieved. Meet the needs of industrial production

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  • Industrial production method for butoconazole nitrate intermediate
  • Industrial production method for butoconazole nitrate intermediate
  • Industrial production method for butoconazole nitrate intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Prepare butoconazole nitrate intermediate 1-chloro-4-(4-chlorophenyl)-2-butanol as follows:

[0037] (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 after the drop to obtain a reaction solution;

[0038] (2) Take the reaction solution obtained in step (1), add the sulfuric acid with a concentration of 25% dropwise at a rate of 2ml / s at 4°C under constant stirring, and stop the dripping when there is no solid residue; leave standstill after stirring at a constant speed for 10min The liquid was separated for 10 minutes; the aqueous phase was discarded, and the organic phase was concentrate...

Embodiment 2

[0041] Compared with Example 1, the difference is only that the step (1) is specifically:

[0042] (1) Get 1.5kg of magnesium powder, 50ml of ether and a catalytic amount of iodine, add 35kg of p-chlorobenzyl ether solution with a concentration of 0.25g / ml dropwise at a rate of 2ml / s at 30°C, The mixture was reacted for 0.5 hour to obtain the p-chlorobenzyl Grignard reagent; then slowly added dropwise 15 kg of epichlorohydrin ether solution with a concentration of 0.33 g / ml, and reacted at 35° C. for 1 hour to obtain the reaction solution.

[0043] The yield of the product of this embodiment is 78.1%.

[0044] After testing, the content of the target product 1-chloro-4-(4-chlorophenyl)-2-butanol is 90.11%, the content of p-chlorotoluene is 7.51%, and the content of chloromethylbenzene is 0.20%, 1, The content of 2-(4-chlorophenyl)ethane was 1.63%, the content of 1-chloro-4-(4-(chloro)benzyl)benzene was 0.19%, the content of 3-chloro-2-(4-chlorobenzyl base)-1-propanol content...

Embodiment 3

[0046] Compared with Example 1, the difference is only that the step (1) is specifically:

[0047] (1) Get 2.5kg of magnesium powder, 50ml of ether and catalytic amount of iodine, add 45kg of p-chlorobenzyl ether solution with a concentration of 0.3g / ml dropwise at a rate of 4ml / s at 40°C, The mixture was reacted for 1.5 hours to obtain the p-chlorobenzyl Grignard reagent; then slowly added dropwise 25 kg of epichlorohydrin ether solution with a concentration of 0.37 g / ml, and reacted at 40° C. for 2 hours to obtain the reaction solution.

[0048] The yield of the product of this embodiment is 75.8%.

[0049] After testing, the content of the target product 1-chloro-4-(4-chlorophenyl)-2-butanol is 83.12%, the content of p-chlorotoluene is 12.33%, and the content of chloromethylbenzene is 0.55%, 1, The content of 2-(4-chlorophenyl)ethane is 2.31%, the content of 1-chloro-4-(4-(chloro)benzyl)benzene is 0.41%, and the content of 3-chloro-2-(4-chlorobenzyl) The content of 1-prop...

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Abstract

The present invention relates to an industrial production method for a butoconazole nitrate intermediate 1-chloro-4-(4-chlorophenyl)-2-butanol. The method comprises the following steps: (1) taking 1.5-2.5 parts of magnesium powder, diethyl ether for initiation and a catalytic amount of acid, slowly dropwise adding 35-45 parts of a p-chlorobenzyl chloride ether solution with the density of 0.2-0.4 g / ml, and performing a reflux reaction after adding dropwise to obtain a p-chlorobenzyl chloride Grignard reagent; slowly dropwise adding 15-25 parts of an epichlorohydrin ether solution with the density of 0.25-0.45 g / ml, and performing a reflux reaction after adding dropwise to obtain reaction liquid; and (2) taking the reaction liquid obtained in step (1), adding dilute sulphuric acid under the condition of ice-bath, standing for layering, retaining an organic phase, concentrating, and rectifying to obtain a product. According to the method provided by the invention, conditions and parameters in the synthetic process are optimized comprehensively, so that the purity and the yield of the product 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-chloro-4-(4-chlorophenyl)-2-butanol. 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 follo...

Claims

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Application Information

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IPC IPC(8): C07C29/64C07C33/46C07D233/60
CPCC07C29/64C07D233/60C07C33/46
Inventor 彭开锋阳苗李三新龚云李伏君文峰球
Owner ZHUZHOU QIANJIN PHARMA
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